Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators

ABSTRACT

This invention provides a compound of formula IA 
     
       
         
         
             
             
         
       
     
     where X=0 or S; Y is 0 or S; q=1 or 0; and other substituents are defined herein. Such compounds can affect the opening of, or otherwise modulate, voltage-gated potassium channels. Such compounds useful for the treatment and prevention of diseases and disorders which are affected by activation or modulation of potassium ion channels. One such condition is seizure disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.11/894,877, filed Aug. 22, 2007, which claims the benefit of U.S.Provisional Application Ser. No. 60/839,941, filed Aug. 23, 2006, eachof which the entire contents are incorporated herein.

FIELD OF THE INVENTION

This invention concerns novel compounds that activate or otherwisemodulate voltage-gated potassium channels. The compounds are useful forthe treatment and prevention of diseases and disorders which areaffected by modulation of potassium ion channels. One such condition isseizure disorders.

BACKGROUND OF THE INVENTION

Epilepsy is a well-known neurological disease, found in about 3% of thepopulation. Approximately 30% of patients with epilepsy do not respondto currently available therapies. Such unfortunate patients—who numberhundreds of thousands of people world-wide * must contend with bothuncontrolled seizures and the resulting narrowing of their options insuch crucial areas of life as health insurance, employment, and driving.

Retigabine (N-[2-amino-4-(4-fluorobenzylamino)phenyl]carbamic acid,ethyl ester) (U.S. Pat. No. 5,384,330) has been found to be an effectivetreatment of seizure disorders and has also been found useful intreating pain. Retigabine has been found to be particularly potent inmodels for the drug-refractory types of epilepsy. Bialer, M. et al.,Epilepsy Research 1999, 34, 1-4 1; Blackburn-Munro and Jensen, Eur. J.Pharmacol. 2003, 460, 109-116; Wickenden, A. D. et al., Expert Opin.Tlier. Patents, 2004, 14(4).

“Benign familial neonatal convulsions,” an inherited form of epilepsy,has been associated with mutations in the KCNQ213 channels. Biervert, C.et al., Science 1998, 27, 403-06; Singh, N. A., et al., Nat. Genet.1998, 18, 25-29; Charlier, C. et al., Nat. Genet. 1998, 18, 53-55;Rogawski, Trends in Neurosciences 2000, 23, 393-398. Subsequentinvestigations have established that one important site of action ofretigabine is the KCNQ2/3 channel. Wickenden, A. D. et al., 11r1Q1.Pharmacol. 2000, 58, 591-600; Main, M. J. et al., Ma! Pharmcol. 2000,58, 253-62. Retigabine has been shown to increase the conductance of thechannels at the resting membrane potential, with a possible mechanisminvolving binding of the activation gate of the KCNQ 2/3 channel.Wuttke, T. V., et al., Mal. Pharmacol. 2005. Additionally, retigabinehas been shown to increase neuronal M currents and to increase thechannel open probability of KCNQ 2/3 channels. Delmas, P. and Brown, D.A. Nat. Rev5 Neuro Sci., vol. 6, 2005, 850-62; Tatulian, L. and Brown,D. A., Physaol, (2003) 549, 57-63.

The seizure type that has been most resistant to therapy is theso-called “complex partial seizure.” Retigabine is active in severalseizure models, including, as indicated above, models fordrug-refractory epilepsy. Because of retigabine's broad spectrum ofactivity and its unusual molecular mechanism, there is hope thatretigabine will be effective in management of several seizure types,including the complex partial seizure, which have been resistant totreatment. Porter, R. J., Nohria, V., and Rundfeldt, C.,Neurotherapeutics, 2007, vol. 4, 149-154.

The recognition of retigabine as a potassium channel opener has inspireda search among compounds with structural features in common withretigabine for other compounds which can affect the opening of, orotherwise modulate, potassium ion channels.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 a-c show pharmacokinetic/pharmacodynamic (PK/PD) responses atthree different dose levels in rat. FIG. 1 a shows PK/PD data at dosagesof 0.75 mg/kg; FIG. 1 b shows PK/PD data at dosages of 1.5 mg/kg, andFIG. 1 c shows PK/PD data at dosages of 3.0 mg/kg.

BRIEF DESCRIPTION OF THE INVENTION

In their efforts to design a potassium channel modulating compound thatis superior to retigabine, shown below, which is a benzyl aminederivative, the present inventors have discovered surprising andexceptionally promising properties in a series of tetrahydroisoquinolinederivatives, specifically, para-.N-(1,2,3,4-tetrahydro)isoquinolylanilides and carbamates, and their several sulfur analogues, of thestructure of formula IA below

These tetrahydroisoquinoline derivatives are, of course, benzyl amineswhich are restricted to particular conformations because the benzylicnitrogen is a member of a second ring fused to the phenyl ring.Moreover, the present inventors have further discovered that replacementof the primary amino group of retigabine with substituents like halogen,CrC₃ alkyl, OC˜—C₃ alkyl, and trifluoromethyl also confers surprisingand desirable properties.

Thus, in one embodiment, this invention provides or contemplates acompound of formula IA

where R₁ and R₂, are, independently, H, CN, halogen, CH₂CN, OH, NO₂,CH₂F, CHF₂, CF₃, CF₂CF₃, C₁-C₆ alkyl, C(═O)C₁-C₆ alkyl; NH₂, NH—C₁-C₆alkyl; N(CrC₆ alkyl)-C₁-C₆ alkyl, NHC(═O)C₁-C₆ alkyl, C(═O)N(CH₃)₂,C(═O)N(Et)2, C(═O)NH₂, C(═O)NH₂—C₁-C₆ alkyl, SO₂NH₂, NHSO₂—C₁-C₆ alkyl;C(═O)OC₁-C₆ alkyl, OC(═O)C₁-C₆ alkyl, OC₁-C₆ alkyl, SC₁-C₆ alkyl, C₃-C₆cycloalkyl, (CH₂)_(m)C₃-C₆ cycloalkyl, C₃-C₆ cycloalkenyl,(CH₂)_(m)C₃-C₆ cycloalkenyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ar,(CH₂)_(m)thienyl, (CH₂)_(m)furyl, (CH₂)_(m)imidazolyl, (CH₂)_(m)pyrazyl,(CH₂)_(m)oxazolyl, (CH₂)_(m)isoxazolyl, (CH₂)_(m)thiazolyl,(CH₂)_(m)isothiazolyl, (CH₂)_(m)phenyl, (CH₂)_(m)pyrrolyl,(CH₂)_(m)pyridyl, or (CH₂)_(m)pyrimidyl, which cycloalkyl and saidcycloalkenyl groups optionally contain one or two heteroatoms selectedindependently from 0, N, and S, and which are optionally substituted asdescribed below; where m is zero, 1, or 2, Ar is a 5- to 10-member mono-or bicyclic aromatic group, optionally containing 1-4 ring heteroatomsselected independently from N, 0, and S; or R₁ and R₂, together with thering carbon atoms to which they are attached, form a 5- or 6-memberfused ring, which ring may be saturated, unsaturated, or aromatic, whichoptionally contains one or two heteroatoms selected independently from0, N, and S, and which is optionally substituted as described below; R′is H, halogen, phenyl, 2-(N,N-dimethylamino)ethyl, CF₃, OCF₃—C₃ alkyl orC₁-C₃ alkyl; R₃ and R₄ are, independently, H, CN, halogen, CF₃, OCF₃,OC₁-C₃ alkyl, or C₁-C₆ alkyl; X═O or S; Y is O or S; q=1 or zero; R₅ isC₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl,CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆cycloalkenyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ar, (CHR₆)_(w)Ar,CH₂(CHR₆)_(w)Ar or (CHR₆)CH₂Ar, where w=zero, 1, 2, or 3, Ar is a 5- to10-member mono- or bicyclic aromatic group, optionally containing 1-4ring heteroatoms selected independently from N, O, and S; R₆ is H orC₁-C₃ alkyl; where all cycloalkyl and cycloalkenyl groups optionallycontain one or two ring heteroatoms selected independently from N, O,and S; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroarylgroups in R₁, R₂, R′, R₃, R₄, R₅, R₆, and Ar are optionally substitutedwith one or two substituents selected independently from C₁-C₃ alkyl,halogen, CN, OH, OMe, OEt, CN, CH₂F, and trifluoromethyl; and where,additionally, all cycloalkyl and heterocycloalkyl groups are optionallysubstituted with a carbonyl group. Such compounds are potassium channelactivators or modulators.

Essentially all combinations of the several variables in formula IA arecontemplated by this invention.

In another embodiment, this invention provides or contemplates acomposition comprising a pharmaceutically acceptable carrier or diluentand at least one of the following: a pharmaceutically effective amountof a compound of formula IA, a pharmaceutically acceptable salt of acompound of formula IA, a pharmaceutically acceptable solvate of acompound of formula IA, and a pharmaceutically acceptable ester of acompound of formula IA.

In yet another embodiment, this invention provides or contemplates apediatric pharmaceutical composition comprising a pharmaceuticallyacceptable carrier or diluent, a syrup for pediatric use, and at leastone of the following: a pharmaceutically effective amount of a compoundof formula IA, a pharmaceutically acceptable salt of a compound offormula IA, a pharmaceutically acceptable ester of a compound of formulaIA, and a pharmaceutically acceptable solvate of a compound of formulaIA.

In yet another embodiment, this invention provides or contemplates achewable tablet, suitable for pediatric pharmaceutical use, comprising apharmaceutically acceptable carrier or diluent, and at least one of thefollowing: a pharmaceutically effective amount of a compound of formulaIA, a pharmaceutically acceptable salt of a compound of formula IA, apharmaceutically acceptable solvate of a compound of formula IA, and apharmaceutically acceptable ester of a compound of formula IA.

In yet another embodiment, this invention provides or contemplates amethod of preventing or treating a disease or disorder which is affectedby activation voltage-gated potassium channels, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of formula IA or a salt or ester or solvate thereof.

This invention includes all tautomers and salts of compounds of thisinvention. This invention also includes all compounds of this inventionwhere one or more atoms are replaced by a radioactive isotope thereof.

This invention provides or contemplates compounds of formula IA abovewhere the group NH—C(═X)—(Y)_(q) R₅ is each of the following:NHC(═O)R_(5,) NHC(═O)OR₅, NHC(═S)R₅, NHC(═S)SR₅, NHC(═S)OR₅, andNHC(═O)SR₅.

Thus, in one embodiment, this invention provides or contemplates acompound of formula IA, where NH—C(═X)—(Y)_(q)—R₅ is NHC(═O)R₅.

In another embodiment, this invention provides or contemplates acompound of formula IA, where NH—C(═X)—(Y)_(q)—R₅ is NHC(═S)R₅.

In another embodiment, this invention provides or contemplates acompound of formula IA, where NH—C(═X)—(Y)_(q-)R₅ is NHC(═S)SR₅.

In another embodiment, this invention provides or contemplates acompound of formula IA, where NH—C(═X)—(Y)_(q)—R₅ is each NHC(═O)OR₅.

In another embodiment, this invention provides or contemplates acompound of formula IA, where NH—C(═X)—(Y)_(q)—R₅ is NHC(═S)OR₅.

In another embodiment, this invention provides or contemplates acompound of formula IA, where NH—C(═X)—(Y)_(q)—R₅ is NHC(═O)SR₅.

In another generic embodiment, this invention provides or contemplates acompound of formula IA, where q is zero and R₅ is C₁-C₆alkyl, or(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is H, methyl, ethyl, orhalogen.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is phenyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is OC₁-C₃ alkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is 2-dimethylaminoethyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is H.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ halogen.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is methyl or ethyl.

In another subgeneric embodiment, R₁ is located as shown below

In another subgeneric embodiment, R₁ is located as shown below

In another subgeneric embodiment, R₁ is located as shown below

In another subgeneric embodiment, R₁ is located as shown below

In another subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below.

In another subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below, where R₅ is C₅-C6alkyl or (CH₂)C₅-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of the structure shown below, where R₅ isC₅-C₆ alkyl or (CH₂)_(W)C₅-C₆ cycloalkyl.

In another specific subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below, where R₃ and R₄are, independently, H, methyl, or methoxy.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below, where R₃ and R₄are, independently, H, methyl, or methoxy, and R₅ is C₅-C₆ alkyl or(CH2)_(w)C₅-C₆ cycloalkyl.

In a still more specific subgeneric embodiment, this invention providesor contemplates a compound of the structure shown below, where R₅ isC₅-C₆ alkyl or (CH₂)_(w)C₅-C6 cycloalkyl.

In another specific subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below, where R₃ and R₄are, independently, H, methyl, or methoxy.

In another specific subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below, where R₃ and R₄are, independently, H, methyl, or methoxy.

In a still more specific subgeneric embodiment, this invention providesor contemplates a compound of the structure shown below, where R₅ isC₅-C₆ alkyl or (CH₂)_(w)C₅-C₆ cycloalkyl.

In another specific subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below, where R₃ and R₄are, independently, H, methyl, Cl, CF₃, OCF₃, or methoxy.

In a still more specific subgeneric embodiment, this invention providesor contemplates a compound of the structure shown below, where R₅ isC₅-C₆ alkyl or (CH₂)_(w)C₅-C₆ cycloalkyl.

In another specific subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below, where R₃ and R₄are, independently, H, methyl, Cl, CF₃, OCF₃, or methoxy.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below, where R is C₅-C₆alkyl or (CH₂)C_(S)-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of the structure shown below, where R₅ isC_(S)-C₆ alkyl or (CH₂)C₅-C₆ cycloalkyl.

In yet another more specific subgeneric embodiment, this inventionprovides or contemplates a compound of the structure shown below, whereR₅ is (CH₃)Ar or C3-C6 alkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below, where R₃ and R₄are, independently, H, methyl, Cl, CF₃, OCF₃, or methoxy.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below, where R₃ and R₄are, independently, H, methyl, Cl, CF₃, OCF₃, or methoxy and R₅ is(CH₂)_(w)Ar or C₃-C₆ alkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of the structure shown below, where R₅ is(CH₂)_(w)Ar or C₃-C₆ alkyl.

In yet another more specific subgeneric embodiment, this inventionprovides or contemplates a compound of the structure shown below, whereR₃ and R₄ are, independently, H, methyl, Cl, CF₃, OCF₃, or methoxy andwhere R is (CH₂)_(w)Ar or C₃-C₆ alkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₂ is H.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₂ is halogen.

In another, more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R₂ is Cl or F.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₂ is trifluoromethyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₃ and R₄ are,independently, H, Cl, methyl, ethyl, trifluoromethyl, or methoxy.

In another, more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where q is zero and R₃ and R₄are Cl, ethyl, methoxy, or methyl.

In another, more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where q is zero and R₃ and R₄are both methyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is methyl, halogen, orH; and R₃ and R₄ are, independently, H, Cl, ethyl, methoxy, or methyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is methoxy; and R₃ andR₄ are, independently, H, Cl, ethyl, methoxy, or methyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R′ is H; and R₃ and R₄are, independently, H, Cl, ethyl, or methyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R is H, q is zero, and R₅is C₁-C₆ alkyl, or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is H; q is 1; Y is 0;and R₅ is C₁-C₆ alkyl, or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is H; q is 1; Y is S;and R₅ is C₁-C₆ alkyl, or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ and R₂ are H and R₅ isC₁-C₆ alkyl, or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ and R₂ are H and R₅ isAr, (CHRs)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ and R₂ are H and R₅ is(CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆alkenyl, or C₂-C₆ alkynyl.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ and R₂ are H and R₅ isCR₆═CH—C₃-C₆ cycloalkyl or CH═CR₆—C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R′ is halogen; and R₃and R₄ arc H, Cl, ethyl, or methyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R′ is Cl or F; and R₃and R₄ are H, Cl, ethyl, or methyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R′ is Cl or F; R₃ and R₄are H, Cl, ethyl, or methyl; and R₅ is C₁-C₆ alkyl, or (CHR₆)_(w)C₃-C₆cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is phenyl, optionallysubstituted.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R′ is 1-phenyl,optionally substituted.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R′ is 4-phenyl,optionally substituted.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R′ is phenyl, optionallysubstituted, and R₅ is C₁-C₆ alkyl, or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R₁ is NH—C₁-C₆alkyl,N(C₁-C₆ alkyl)-C₁-C₆ alkyl, C(═O)NH—C₁-C₆ alkyl, NH—C(═O)C₁-C₆ alkyl;O—C₁-C₆ alkyl, C(═O)—C₁-C₆ alkyl, C(═O)—OC₁-C₆ alkyl, or OC(═O)C₁-C₆alkyl; R′ is phenyl, optionally substituted, and R₅ is C₁-C₆ alkyl, or(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is H, methyl, or ethyl;and R₁ is NH—C₁-C₆ alkyl, N(C₁-C₅ alkyl)-C₁-C₆ alkyl, C(═O)NH—C₁-C₆alkyl, or NH—C(═O)C₁-C₆ alkyl.

In yet another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R′ is H, methyl, or ethyl;and R₁ is C(═O)OC₁-C₆ alkyl, OC(═O)C₁-C₆ alkyl, or OC₁-C₆ alkyl.

In another specific subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is H, methyl, methoxy,or halogen, and R′ is methyl or ethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R₁ is H, methyl,methoxy, or halogen, and R′ is phenyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R₁ is H, methyl,methoxy, or halogen, and R′ is F.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is methoxy,methoxymethyl, ethoxytnethyl, or methoxyethyl.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is methoxy,methoxymethyl, ethoxymethyl, or methoxyethyl; R₂ is H, methyl, orhalogen; and R₃ is methyl or Cl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R′ is 4-phenyl,optionally substituted, and R₂ is H, methyl, methoxy, or halogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R′ is CF₃ or C₁-C₃alkyl, and R₂ is H, methyl, methoxy, or halogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R′ is methoxy, and R₂ isH, methyl, methoxy, or halogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R′ is 2-dimethylaminoethyl, and R₂ is H, methyl, methoxy, or halogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where q is zero, R₂ is H,methyl, methoxy, or halogen, R′ is 1-phenyl, optionally substituted; andR₃ and R₄ are H, Cl, ethyl, or methyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where q is zero, R₂ is H,methyl, methoxy, or halogen, R′ is 4-phenyl, optionally substituted; andR₃ and R₄ are H, Cl, ethyl, or methyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where q is zero, R₂ is H,methyl, methoxy, or halogen; R′ is CF₃ or C₁-C₃ alkyl; and R₃ and R₄ areH, Cl, ethyl, or methyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where q is zero, R₂ is H,methyl, methoxy, or halogen; R′ is methoxy; and R₃ and R₄ are H, Cl,ethyl, or methyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where q is zero; R′ is(2-dimethylamzno)ethyl; R₂ is H, methyl, methoxy, or halogen; and R₃ andR₄ are H, Cl, ethyl, or methyl.

In a more specific sub-generic embodiment, the invention provides orcontemplates a compound of formula IA-1 below.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IA-2 below.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IA-3 below.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IA-4 below.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IA-5 below.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-2 or formula IA-3, where R₂ is H,alkyl, or halogen; and R₅ is C₁-C₆ alkyl, (CHR₆)C₃-C₆ cycloalkyl,(CHR₆)_(W)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1 or formula IA-3, where R₁ is(CH₂),C₃-C₆ cycloalkyl; R₂ is H, alkyl, or halogen; and R₅ is C₁-C₆alkyl, (CHR₆)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1 or formula IA-3, where R₁ ismethoxy, methoxymethyl, or methoxyethyl; R₂ is H, alkyl, or halogen; andR₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₅cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆ cycoalkyl.

In yet another more specific subgeneric embodiment, this inventionprovides or contemplates a compound of formula IA-2, where R₅ is C₁-C₆alkyl, (CHR₆)C₃-C₆ cycloalkyl, (CHR₆)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)C₃-C₆ cycloalkyl.

In yet another more specific subgeneric embodiment, this inventionprovides or contemplates a compound of formula IA-2, where R₅ is Ar,(CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)CH₂Ar.

In yet another more specific subgeneric embodiment, this inventionprovides or contemplates a compound of formula IA.-2, where R₅ isCR₆—CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In yet another more specific subgeneric embodiment, this inventionprovides or contemplates a compound of formula IA-3, where R₂ and R′ areH; R₃ is methyl; and R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl,(CHR₆)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)C₃-C₅ cycloalkyl.

In a still more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is H, F, Cl, Br,methoxy, methoxymethyl, ethoxymethyl, methoxyethyl, or trifluoromethyl;R₃ is methyl; and R is C₄-C6₆alkyl, (CHR₆)_(w)CH₂C₅-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₅-C₆ cycloalkyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates a compound of formula IA-2, where R₅ is C₄-C₆alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; andR₁ is H, F, Cl, Br, methoxy, methoxymethyl, ethoxymethyl, methoxyethyl,or trifluoromethyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates a compound of formula IA-3, where R₁ is H, F,Cl, Br, methoxy, methoxymethyl, ethoxymethyl, methoxyethyl, ortrifluoromethyl; R₂ is H, methyl, or F; R′ is H or methyl; R₃ is methyl;and R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆cycloalkyl.

In another more generic embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ is (CH₂)_(m)C₃-C₆cycloalkyl, C₃-C₆cycloallcenyl, or (CH₂)mC₃-C₆ cycloalkenyl; R′ ishalogen; and R₃ is methyl or Cl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is (CH₂)_(m)C₃-C₆cycloalkyl, C₃-C₆ cycloalkenyl, or (CH₂)_(m)C₃-C₆ cycloalkenyl; and R.is F or Cl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is methoxy,methoxymethyl, ethoxymethyl; or methoxyethyl; R₂ is H or F; R₃ ismethyl; R₄ is methyl or Cl; and R₅ is (CHR₆)_(w)C₅-C₆ cycloalkenyl or(CHR₆)_(w)Ar.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is phenyl,optionally substituted.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is methyl,halomethyl, ethyl, or haloethyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R′ is2-(dimethylamino)ethyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R′ is 1-methyl or1-ethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R′ is 1-fluoro, R₅ isC₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, or trifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R′ is 4-fluoro, R₅ isC₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, or trifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is (CH₂)_(m)imidazolyl, (CH₂)_(m)pyrazyl, (CH₂)_(m) furyl, (CH₂)_(m) thienyl,(CH₂)_(m)oxazolyl, (CH₂)_(m)isoxazolyl, (CH₂)_(m)thiazolyl,(CH₂)_(m)isothiazolyl, (CH₂)_(m)phenyl, (CH₂)_(m)pyrrolyl,(CH₂)_(m)pyridyl, or (CH₂)_(m)pyrimidyl; and R₂ and R′ are H.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is(CH₂)_(m)imidazolyl, (CH₂)_(m)pyrazyl, (CH₂)_(m) furyl, (CH₂)_(m)thienyl, (CH₂)_(m)oxazolyl, (CH₂)_(m)isoxazolyl, (CH₂)_(m)thiazolyl,(CH₂)_(m)isothiazolyl, (CH₂)_(m)phenyl, (CH₂)_(m)pyrrolyl,(CH₂)_(m)pyridyl, or (CH₂)_(m)pyrimidyl; and R′ is 4-phenyl, optionallysubstituted.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R′ is CF₃ or C₁-C₃alkyl; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R′ is 4-methyl or4-ethyl; and R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R′ is methoxy orethoxy; and R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R′ is 1-phenyl,optionally substituted; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl,or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R′ is 4-phenyl,optionally substituted; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl,or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R′ is CF₃ or C₁-C₃alkyl; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C_(S)-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R′ is 4-methyl or4-ethyl; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-I, where R′ is methoxy orethoxy, R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)C₅-C₆cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, or trifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-4, where R₁ is H, F, Cl, Br,methoxy, or trifluoromethyl; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br,methoxy, or trifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-4, where R₂ is H, F, or methyl;R₅ is C₄-C₆ alkyl, (CHR₆),_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)C₅-C₆cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, or trifluoromethyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-2, where R′ is H.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-2, where R′ is halogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R′ is F.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R′ is methyl or ethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R′ is methyl or ethyl;R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, or trifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R′ is halogen; R₅ isC₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)C₅-C₆ cycloalkyl;and R₁ is H, F, Cl, Br, methoxy, or trifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R′ is H; R₅ is C₄-C₆alkyl, (CHR₆)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁is H, F, Cl, Br, methoxy, or trifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R′ is 1-phenyl,optionally substituted.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R′ is 4-phenyl,optionally substituted.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R′ is CF₃ or C₁-C₃alkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R′ is H; R₅ is C₄-C₆alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)C₅-C₆ cycloalkyl; and R₁is H, F, Cl, Br, methoxy, or trifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R′ is F; R₅ is C₄-C₆alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; andR₁ is H, F, Cl, Br, methoxy, or trifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R′ is 1-phenyl,optionally substituted; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl,or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R′ is 4-phenyl,optionally substituted; R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl,or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R′ is CF₃ or C₁-C₃alkyl; R₅ is C4-C6 alkyl, (CHR₆)_(w)C₅-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₅-C₆ cycloalkyl; and R₁ is H, F, Cl, Br, methoxy, ortrifluoromethyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ and R₂, are,independently, H, CN, F, Cl, Br, CH₂CN, OCH₃, CH₂OCH₃, CH₂CH₂OCH₃,CH₂OCH₂CH₃; CH₂F, CHF₂, CF₃, CF₂CF₃, or C₁-C₆ alkyl and R₅ is C₁-C₆alkyl or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl, where w=0, 1, or 2.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates a compound of formula IA-1, R₁ is H, CN, F, Cl,Br, CH₂CN, OCH₃, CH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂F, CHF₂, CF₃,CF₂CF₃, or C₁-C₆ alkyl; R₂ is H, F, Cl, or methyl; R₃ is methyl orchloro; and R₅ is C₁-C₆ alkyl or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl, where R₆is H or methyl and w=1 or 2.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R₅ is Ar, (CHR₆)_(w)Ar,CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-2, where R₅ is Ar, (CHR₆)_(w)Ar,CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar₁.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-3, where R₅ is Ar, (CHR₆)_(w)Ar,CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar.

In another more specific subgeneric embodiment, this invention providesor contemplates compounds of formula IA-1, IA-2, IA-3, IA-4, or IA-5,where R₁ and R₂, are, independently, methyl, ethyl, F, Cl, CF₃, methoxyor methoxymethyl, R′ is methyl, and R₅ is C₄-C₆ alkyl, (CHR₆)_(w)C₅-C₆cycloalkyl, or CH₂(CHR₆)_(w)C₅-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R₅ is CR₆═CH—C₃-C₆cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₅ is haloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₅ is haloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA•2, where R₅ is haloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-3, where R₅ is haloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₅ is methoxy alkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₅ is cyano alkyl.

In a more specific subgeneric embodiment, the invention provides orcontemplates a compound of formula IA-4, where R₅ is halo alkyl.

In a more specific subgeneric embodiment, the invention provides orcontemplates a compound of formula IA, where R₅ is CH₂-cycloalkyl orCH₂CH₂-cycloalkyl.

In a more specific subgeneric embodiment, the invention provides orcontemplates a compound of formula IA-4, where R₅ is CH₂-cycloalkyl orCH₂CH₂-cycloalkyl_(—)

In a more specific subgeneric embodiment, the invention provides orcontemplates a compound of formula IA-5, where R₅ is CH₂-cycloalkyl orCH₂CH₂-cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₃ and R₄ are chloro,methoxy, or methyl and R₅ is CH₂-cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₃ and R₄ are chloro,methoxy, or methyl and R₅ is haloalkyl, hydroxyalkyl, or methoxyalkyl.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₃ and R₄ are chloro,methoxy, or methyl and R₅ is methoxy alkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-2, where R₃ and R₄ are chloro,methoxy, or methyl and R₅ is chloroalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-2, where R₃ and R₄ are chloro,methoxy, or methyl and R₅ is methoxyalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₃ and R₄ are both methyland R₅ is 2-(2-halo cyclopentyl)ethyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₃ and R₄ are both methyland R₅ is 2-(2-furyl)ethyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₃ and R₄ are both methyland R₅ is 2-(2-tetrahydrofuryl)ethyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₃ and R₄ are both methyland R₅ is 2-phenyl ethyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₃ and R₄ are both methyland R₅ is 3-phenyl propyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₃ and R₄ are both methyland R₅ is 2-phenyl propyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl; R′ is halogen or C₁-C₃ alkyl; and R₁ ishalogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl; R′ is halogen or C₁-C₃ alkyl; R₂ is H orhalogen; and R₁ is halogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl; R′ is phenyl, optionally substituted; R₂is H or halogen; and R₁ is halogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₅ cycloalkyl; R′ is halogen or C₁-C₃ alkyl; R₂ is H orhalogen; and R₁ is halogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl; R′ is halogen or C₁-C₃ alkyl; and R₁ ishalogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl; R′ is halogen or C₁-C₃ alkyl; and R₁ ishalogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R₅ is CR₆═CH—C₃-C₆cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R₅ is Ar, (CHR₆)_(w)Ar,CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar₁.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₁ is haloalkyl; R₂ isH or F; R₃ and R₄ are Cl, methoxy, or methyl; and R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)CH₂C₃-C₆ cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where R₁ is C₁-C₃ alkyl,halogen, or haloalkyl; R₂ is H or F; R₃ and R₄ are H, methyl, or Cl; andR₅ is CH₂CR₆—C₃-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆cycloalkenyl, C₄-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is C₁-C₃ alkyl,halogen, or haloalkyl; R₂ is H or F; R₃ and R₄ are H, methyl, or Cl; andR₅ is CH₂CR₆—C₃-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆cycloalkenyl, C₄-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₁ is C₁-C₃ alkyl,halogen, or haloalkyl; R₂ is H or F; R₃ and R₄ are H, methyl, or Cl; andR₅ is CH₂CR₆—C₃-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆cycloalkenyl, C₄-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C6 alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is C₁-C₃ alkyl,halogen, or haloalkyl; R₂ is H or F; R₃ and R₄ are H, methyl, or Cl; andR₅ is CH₂CR₆—C₃-C₆ cycloalkyl, or C₂-C₆ alkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₁ is C₁-C₃ alkyl,halogen, or haloalkyl; R₂ is H or F; R₃ and R₄ are H, methyl, or Cl; andR₅ is CH₂CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₁ is halogen orhaloalkyl; R₂ is H or F; and R₅ is CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₁ is halogen orhaloalkyl; R₂ is H or F; and R₅ is CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆cycloalkenyl, C₂-C6 alkenyl, or C₂-C₆ alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₁ is halogen orhaloalkyl; R₂ is H or F; R₃ and R₄ are Cl, methoxy, or methyl; and R₅ isC₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl,or CH₂(CHR₆)C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₁ is halogen orhaloalkyl; R₂ is H or F; and R₅ is CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₁ is methyl, fluoro,or fluoroalkyl; R₂ is H or F; and R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₁ is Cl, F, or CF₃;R₂ is H or F; R′ is H or CH₃; and R₅ is CR₆═CH—C₃-C₆ cycloalkyl,CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)C₅-C₆cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₁ is Cl, F, or CF₃;R₂ is H or F; R′ is H or CH₃; and R₅ is Ar, (CHR₆)_(w)Ar,CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-4, where R₃ and R₄ are H,methyl, or Cl; and R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl,(CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-5, where R₃ and R₄ are H,methyl, or Cl; and R₅ is CR₆═CH—C₃-C₆ cycloalkyl, CH^(—)CR₆—C₃-C₆cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₃ and R₄ are H,methyl, or Cl; and where R₁ and R₂, on adjacent carbons, form asix-membered ring.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₃ and R₄ are H,methyl, or Cl; where R₅ is C₂-C₆ alkyl, CH₂—C₅-C₆ cycloalkyl,CH₂CH₂—C₅-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, or C₂-C₆ alkenyl; and where R₁ and R₂, are on adjacentcarbons, and are both other than H.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R and R₄ are H,methyl, or Cl; where R₅ is C₂-C₆ alkyl, CH₂—C₅-C₆ cycloalkyl,CH₂CH₂—C₅-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, or C₂-C₆ alkenyl; and where R₁ and R₂, on adjacent carbons,are both halogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₃ and R₄ are H,methyl, or Cl; where R₅ is C₂-C₆ alkyl, CH₂—C₅-C₆ cycloalkyl,CH₂CH₂—C₅-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, or C₂-C₆ alkenyl; and where R₁ and R₂, on adjacent carbons,are both fluorine.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R′ is F, methyl, or H; R₃and R₄ are H, methyl, or Cl; and R₅ is C₁-C₆ alkyl,(CHR₆)_(w)C₃-C₆cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆cycloalkyl, orCH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R′ is F, methyl, or H;R₅ is CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, (CHR₆)_(w)C₅-C₆cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R′ is halogen and R₅is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar₁.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ and R₂ are on adjacentcarbon atoms and are both other than H.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ and R₂, on adjacentcarbon atoms are, independently trifluoromethyl or halogen; and where R₅is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₅ is (CHR₆)_(w)C₅-C₆cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is halogen and R₂is H, or R₁ and R₂, on adjacent carbon atoms are, independentlytrifluoromethyl or halogen; and where R₅ is CR₆═CH—C₃-C₆ cycloalkyl,CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₅ is Ar, (CHR₆)_(w)Ar,CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar₁.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is halogen ortrifluoromethyl and R₂ is H, or R₁ and R₂, on adjacent carbon atoms are,independently trifluoromethyl or halogen; and where R₅ is Ar,(CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where X is S, q=1, Y is O, andR₅ is C₁-C₆ alkyl, (CHR6)_(w)C₃-C₆ cycloalkyl, (CHR6)_(w)CH₂C₃-C₆cycloalkyl, or CH₂(CHR6)_(w)C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where X is S, q=1, Y is O, andR₅ is CR6=CH—C₃-C₆ cycloalkyl, CH═CR6-C₃-C₆ cycloalkyl, (CHR6)_(w)C₅-C₆cycloalkenyl, CH₂(CHR6)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where X is S, q=1, Y is O, andR₅ is Ar, (CHR6)_(w)Ar, CH₂(CHR6)_(w)Ar, or (CHR6)_(w)CH₂Ar.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where X is S, q=zero, and R₅is C₁-C₆ alkyl, (CHR6)_(w)C₃-C₆ cycloalkyl, (CHR6)_(w)CH₂C₃-C₆cycloalkyl, or CH₂(CHR6)_(w)C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, where X is S, q=zero, and R₅is CR₅═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆cycloalkenyl, CH₂(CHR₆)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-2 where R₅ is C₁-C₆ alkyl or(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-3, where R₅ is C₁-C₆ alkyl or(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-2, where R₁ is halogen ortrifluoromethyl and R₂ is H or R₁ and R₂, on adjacent carbon atoms, are,independently, halogen or trifluoromethyl; and R₅ is C₁-C₆ alkyl or(CHR₆)_(w)C₃-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-3, where R₁ is halogen ortrifluoromethyl and R₂ is H or R₁ and R₂, on adjacent carbon atoms, are,independently, halogen or trifluoromethyl; and R₅ is Cr—C_(b) alkyl or(CHRo)C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R₁ and R₂ are,independently, methyl, methoxy, trifluoromethyl, F, Cl, or H; and R₅ isC₁-C₆ alkyl or (CHR₆)C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₁ and R₂ are,independently, methyl, methoxy, trifluoromethyl, F, Cl, or H; R′ is H;and R₅ is C₁-C₆ alkyl or (CHR₆)_(w)C₃-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula. IA-1 or IA-2 or IA-3, where R₁ ishalogen, C₁-C₆, alkyl, mono-halo C₁-C₆ alkyl, CN, di-halo C₁-C₆ alkyl,CF₃, CN, or O—C₁-C₆ alkyl; R′ is methyl or ethyl; and R₅ is C₅-C₆ alkylor CH₂—C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1 or IA-2 or IA-3, where R₁ isH, halogen, cyano, CF₃, or methoxy, R₂ is H, F, or methyl, R′ is H,halogen, methyl, ethyl, or methoxy, and R₅ is C₅-C₆ alkyl or CH₂—C₃-C₆cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is F, Cl, or CF₃; R₂ isH; and R′ is halogen, methyl, ethyl, or methoxy; R₃ and R₄ are H,methyl, or Cl; and R₅ is C₅-C₆ alkyl or CH₂—C₃-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is halogen or CF₃; R₂ isH, F, or methyl, R′ is phenyl; R₃ and R₄ are H, methyl, or Cl; and R₅ isC₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is halogen or CF₃; R₂ isH, F, or methyl, R′ is halophenyl; R₃ and R₄ are H, methyl, or Cl; andR₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is NH₂, NH—C₁-C₆ alkyl;N(C₁-C₆ alkyl)-C₁-C₆ alkyl, NHC(═O)C₁-C₆ alkyl, C(═O)N(CH₃)₂,C(═O)N(Et)₂, C(═O)NH₂, C(═O)NH—C₁-C₆ alkyl, SO₂NH₂, NHSO₂—C₁-C₆ alkyl.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of formula IA where R₁ is NH₂, NH—C₁-C₆ alkyl;or N(C₁-C₆ alkyl)-C₁-C₆ alkyl; and R₂ is H or halogen.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA where R₁ is NHC(═O)C₁-C₆ alkyl,C(═O)N(CH₃)₂, C(═O)N(Et)₂, C(═O)NH₂, or C(═O)NH—C₁-C₆ alkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1 where R₁ is NHC(═O)C₁-C₆alkyl, C(═O)N(CH₃)₂, C(═O)N(Et)₂, C(═O)NH₂, or C(═O)NH—C₁-C₆ alkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1 where R₁ is SO₂NH₂ orNHSO₂—C₁-C₆ alkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2 where R₁ is SO₂NH₂ orNHSO₂—C₁-C₆ alkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is C(═O)OC₁-C₆ alkyl,OC(═O)C₁-C₆ alkyl, OC₁-C₆ alkyl, or SC₁-C₆ alkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is (CH₂)_(m)C₃-C₆cycloalkenyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is CH₂OCH₃, CH₂OCH₂CH₃,OC₁-C₆ alkyl, or SC₁-C₆ alkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is C(═O)OC₁-C₆alkyl, OC(═O)C₁-C₆ alkyl, OC₁-C₆ alkyl, or SC₁-C₆ alkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ is CH₂OCH₃,CH₂OCH₂CH₃, OC₁-C₆ alkyl, or SC₁-C₆ alkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is C(═O)OC₁-C₆alkyl, OC(═O)C₁₋C₆ alkyl, OC₁-C₆ alkyl, or SC₁-C₆ alkyl; R₂ is H, F, ormethyl, R′ is halogen or methyl; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is NH₂, NH—C₁-C₆alkyl; or N(C₁-C₆ alkyl)-C₁-C₆ alkyl; R₂ is H, F, or methyl, R′ ishalogen or methyl; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is NHC(═O)C₁-C₆alkyl, C(═O)N(CH₃)₂, C(═O)N(Et)₂, C(═O)NH₂, C(═O)NH—C₁-C₆ alkyl, SO₂NH₂,or NHSO2-C₁-C₆ alkyl; R₂ is H, F, or methyl, R′ is halogen or methyl;and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is C₂-C₆ alkynyl,optionally substituted.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ and R₂ form a fused,nitrogen-containing ring.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ and R₂ form a fused,oxygen-containing ring.

In another sub generic embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ and R₂ form a fusedthiazolo or isothiazolo group.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ and R₂ form a fusedcyclopentane, optionally substituted.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ and R₂ form a fusedcyclohexane, optionally substituted.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1 or IA-2, where R₁ and R₂ form afused, nitrogen-containing ring.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1 or IA-2, where R₁ and R₂ form afused, oxygen-containing ring.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1 or IA-2, where R₁ and R₂ form afused thiazolo or isothiazolo group.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1 or IA-2, where R₁ and R₂ form afused cyclopentane, optionally substituted.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1 or IA-2, where R₁ and R₂ form afused cyclohexane, optionally substituted.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1 or IA-2, where R₁ and R₂ form afused, nitrogen-containing ring; and R₅ is C₅-C₆ alkyl or CH₂-c₅-C₆cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1 or IA-2, where R₁ and R₂ form afused, oxygen-containing ring; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1 or IA-2, where R₁ and R₂ form afused thiazolo or isothiazolo group; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1 or IA-2, where R₁ and R₂ form afused cyclopentane, optionally substituted; and R₅ is C₅-C₆ alkyl orCH₂—C₅-C₆ cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1 or IA-2, where R₁ and R₂ form afused cyclohexane, optionally substituted; and R₅ is C₅-C₆ alkyl orCH₂—C₅-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is halogen; R₂ isH, F, or methyl, R′ is halogen or methyl; and R₅ is C₅-C₆ alkyl orCH₂—C₅-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is halogen; R₂ isH, F, or methyl, R′ is 2-(dimethylamino)ethyl; and R₅ is C₅-C₆ alkyl orCH₂—C₅-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, where R₁ is halogen; R₂ isH, halogen, or methyl, R′ is H; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R₁ is halogen; R₂ is Hor methyl, R′ is halogen or methyl; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆cycloalkyl.

C(═O)OC₁-C₅ alkyl, OC(═O)C₁-C₆ alkyl, OC₁-C₆ alkyl In another morespecific subgeneric embodiment, this invention provides or contemplatesa compound of formula IA-1, In another more specific subgenericembodiment, this invention provides or contemplates a compound offormula IA-1, where R₁ is trifluoromethyl; R₂ is H or methyl, R′ ishalogen or methyl; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R₁ where R₁ istrifluoromethyl; R₂ is H or methyl, R′ is halogen or methyl; and R₅ isC₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-3, where R₁ where R₁ istrifluoromethyl; R₂ is H or methyl, R′ is halogen or methyl; and R₅ isC₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-4 or IA-5, where R₁ where R₁ istrifluoromethyl; R₂ is H or methyl, R′ is halogen or methyl; and R₅ isC₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-2, where R₁ is trifluoromethyl;R₂ is F; R′ is halogen or methyl; and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆cycloalkyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ or R₅ is CH₂Ar orCH₂CH₂—Ar, where Ar is phenyl, pyridyl, pyrrolyl, imidazolyl, oxazolyl,or thiazolyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is F.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is Cl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is Br.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ is F.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ is Cl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ is Br.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ is F and R₂ is H,OCH₃, or F.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ is F; R₃ and R₄ areboth methyl; and R′ is H.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ is CF₃; R₃ and R₄ areboth methyl; and R′ is H.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ and R₂ are both F.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is mono-, di-, ortri-halomethyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is CH₂F, CHF₂, or CF₃.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is CH₂Cl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ is CH₂Br.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ and R₂ are both F; R₃and R₄ are both methyl; and R′ is H.

In another subgeneric embodiment, this invention, provides orcontemplates a compound of formula IA-2, where R₁ is F.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-2, where R₁ and R₂ are both F.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-3, where R₁ is F.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-3, where R₁ and R₂ are both F.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ or R₅ is CH₂Ar orCH₂CH₂—Ar, where Ar is isoxazolyl or isothiazolyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ or R₅ is CH₂Ar orCH₂CH₂—Ar, where Ar is quinolyl or isoquinolyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ or R₅ is CH₂Ar orCH₂CH₂—Ar, where Ar is pyrimidyl or purinyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ or R₅ is CH₂Ar orCH₂CH₂—Ar, where Ar is indolyl, isoindolyl, or benzimidazolyl.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA, where R₁ or R₅ is CH₂Ar or CH₂CH₂—Ar, where Aris halo phenyl.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ or R₅ is CH₂Ar orCH₂CH₂—Ar, where Ar is dihalophenyl or dihalopyridyl.

In another more specific embodiment, invention provides or contemplatesa compound of formula IA, where R₁ or R₅ is CH₂Ar or CH₂CH₂—Ar, where Aris mono- or di-halothienyl, mono- or di-halofuryl, mono- ordi-halobenzothienyl, or mono- or di-halobenzofuryl.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ or R₅ is CH₂Ar orCH₂CH₂—Ar, where Ar is o-, m-, or p-xylyl or o-, m-, or p-anisyl.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IA, where R₁ or R₅ is CH₂Ar orCH₂CH₂—Ar, where Ar is m- or p-cyanophenyl or m- or p-cyanomethylphenyl.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, in which R₃ and R₄ are halogen,CF₃, or C₁-C₃ alkyl and R₅ is C₁-C₆ alkyl, where the alkyl group issubstituted with one or two groups selected, independently, from OH,OMe, OEt, F, CF₃, Cl, or CN.

In another sub generic embodiment, this invention provides orcontemplates a compound of formula IA, in which R₃ and R₄ are halogen,CF₃, OCF₃, C₁-C₃ alkyl, or OC₁-C₃ alkyl, and R₅ is (CH₂)_(w)C₃-C₆cycloalkyl, where w is 1 or 2, where the cycloalkyl group is substitutedwith Me, OH, OMe, OEt, F, CF₃, Cl, or CN.

In a more specific subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, in which R₃ and R₄ are halogen,CF₃, or C₁-C₃ alkyl, and R₅ is (CH₂)_(w)—C₅-C₆ cycloalkyl, optionallysubstituted, or (CH₂)_(w)—C₅-C₆ heterocycloalkyl, optionallysubstituted.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IA-I, where R₁ is CH₂phenyl orCH₂CH₂-phenyl.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₁ is Ar, CH₂Ar orCH₂CH₂—Ar, where Ar is 3,5-dichlorophenyl or 3,5-difluorophenyl.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-1, where R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR₆)_(w)CH₂Ar, where Ar is phenyl or pyridyl; R₃ and R₄ are H orC₁-C₆ alkyl, unsubstituted or substituted with one or two groupsselected from OH, OMe; and R₆ is CN, CH₂CN, or halogen.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-1, where R₅ is Ar, (CHR₆)_(w)Ar,CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar, where Ar is phenyl or pyridyl; andR₁ is F, CH₂F, CHF₂, CF₃, or CF₂CF₃.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-1, where R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR₆)_(w)CH₂Ar, where Ar is phenyl or pyridyl, and R₁ is OC₁-C₆alkyl or C(═O)C₁-C₆ alkyl.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-1, where R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR6)_(w)CH₂Ar, where Ar is phenyl or pyridyl, and R₁ is C(═O)OC₁-C₆alkyl or OC(═O)C₁-C₆ alkyl.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-1, where R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR₆)_(w)CH₂Ar, where Ar is phenyl or pyridyl, R₁ is C₂-C₆ alkenylor C₂-C₆ alkynyl, q is 1, and X and Y are both O.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-1, where R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR₆)CH₂Ar, Ar is phenyl or pyridyl, and R₁ is SC₁-C₆ alkyl.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-1, where R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR₆)_(w)CH₂Ar, where Ar is phenyl or pyridyl, R₃ and R₄ are H, Cl,methoxy, or C₁-C₃ alkyl, and R₁ is C₁-C₆ alkyl.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-2, where R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR₆)_(w)CH₂Ar, where Ar is phenyl or pyridyl; R₃ and R₄ are H, Cl,methoxy, or C₁-C₂ alkyl, unsubstituted or substituted with one or twogroups selected from OH, OMe; and R₁ is CN, CH₂CN, or halogen.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA-2, where R₅ is Ar, (CHR₆)_(w)Ar,CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar, where Ar is phenyl or pyridyl; andR₁ is F, CH₂F, CHF₂, CF₃, or CF₂CF₃.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-1, where R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR₆)CH₂Ar, where Ar is phenyl or pyridyl, and R₁ is OC₁-C₆ alkyl orC(═O)C₁-C₆ alkyl.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-2, where R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR₆)_(w)CH₂Ar, where Ar is phenyl or pyridyl, and R₁ is OC₁-C₆alkyl or C(═O)C₁-C₆ alkyl.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-3, where R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR₆)_(w)CH₂Ar, where Ar is phenyl or pyridyl, and R₁ is OC₁-C₆alkyl or C(═O)C₁-C₆ alkyl.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-3, where R′ is phenyl or methoxy, R₂ is H, and R₅is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar, or (CHR₆)_(w)CH₂Ar, where Ar isphenyl or pyridyl, and R₁ is C(═O)OC₁-C₆ alkyl or OC(═O)C₁-C₆ alkyl.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-2, where R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR₆)CH₂Ar, Ar is phenyl or pyridyl, and R₁ is SC₁-C₆ alkyl.

In a more specific embodiment, this invention provides or contemplates acompound of formula IA-2, where R₅ is Ar, (CHR₆)_(w)Ar, CH₂(CHR₆)_(w)Ar,or (CHR₆)CH₂Ar, where Ar is phenyl or pyridyl, R₃ and R₄ are H or C₁-C₃alkyl, and R₁ is C₁-C₆ alkyl.

In another embodiment, this invention provides or contemplates a methodof treating or preventing a disease, disorder, or condition that isaffected by modulation of potassium ion channels in a patient comprisingadministration of a compound of formula IA in an amount of up to 2000 mgper day.

In another embodiment, this invention provides or contemplates a methodof treating or preventing a disease, disorder, or condition that isaffected by modulation of potassium ion channels in a patient comprisingadministration of a compound of formula IA in an amount of from about 10mg to about 2000 mg per day.

In a more specific embodiment, this invention provides or contemplates amethod of treating or preventing a disease, disorder, or condition thatis affected by modulation of potassium ion channels in a patientcomprising administration of a compound of formula IA-i in an amount ofup to about 2000 mg per day.

In a more specific embodiment, this invention provides or contemplates amethod of treating or preventing a seizure disorder in a patientcomprising administration of a compound of formula IA in an amount of upto about 2000 mg per day.

In another embodiment, this invention provides or contemplates a methodof treating or preventing a seizure disorder in a patient comprisingadministration of a compound of formula IA in an amount of from about 10mg per day to about 2000 mg per day.

In another embodiment, this invention provides or contemplates a methodof treating or preventing a seizure disorder in a patient comprisingadministration of a compound of formula IA in an amount of from about300 mg per day to about 2000 mg per day.

In another embodiment, this invention provides or contemplates a methodof treating or preventing a seizure disorder in a patient comprisingadministration of a compound of formula IA in an amount of from about300 mg per day to about 1200 mg per day.

In another more specific embodiment, this invention provides orcontemplates a method of treating or preventing a seizure disorder in apatient comprising administration of a compound of formula IA-1 in anamount of up to 2000 mg per day.

In another embodiment, this invention provides or contemplates a methodof treating or preventing a seizure disorder in a patient comprisingadministration of a compound of formula IA-1 in an amount of from about10 mg per day to about 2000 mg per day.

In another embodiment, this invention provides or contemplates a methodof treating or preventing a seizure disorder in a patient comprisingadministration of a compound of formula IA-1 in an amount of from about300 mg per day to about 2000 mg per day.

In another embodiment, this invention provides or contemplates a methodof treating or preventing a seizure disorder in a patient comprisingadministration of a compound of formula IA-1 in an amount of from about300 mg per day to about 1200 mg per day.

In another embodiment, this invention provides or contemplates a methodof treating or preventing a disease, disorder, or condition that isaffected by modulation of at least one potassium ion channel selectedfrom KCNQ2/3, KCNQ4, and KCNQ5 in a patient comprising administration ofa compound of formula IA-1. In such embodiments, KCNQ1 is substantiallyunaffected.

In another embodiment, this invention provides or contemplates a methodof treating or preventing a disease, disorder, or condition that isaffected by modulation of at least one potassium ion channel selectedfrom KCNQ2/3, KCNQ4, and KCNQ5 in a patient comprising administration ofcompound A:

in an amount of from about 10 mg to about 2000 mg per day to a patientin need thereof. In such embodiments, KCNQ1 is substantially unaffected.

DETAILED DESCRIPTION OF INVENTION

As contemplated by this invention, compounds of formula IA are designedfor oral or intravenous dosing of up to 2000 mg per day. Yet the highactivities of many of these compounds indicate that dosing of less than1200 mg per day—the current anticipated dosing level of retigabine inadults—is possible. Thus, this invention comprises tablets, capsules,solutions, and suspensions of compounds of formula IA which areformulated for oral administration. Similarly, solutions and suspensionssuitable for oral pediatric administration, comprising, in addition tocompounds of formula IA, a syrup such as sorbitol or propylene glycol,among many other examples, are also contemplated. More specifically,solutions and suspensions comprising, in addition to compounds offormula IA, a syrup such as sorbitol or propylene glycol, along withcolorants and flavorings suitable for oral pediatric administration, arealso contemplated. Additionally, both chewable and non-chewable tabletscomprising compounds of formula IA, along with pharmaceuticallyacceptable tabletting agents and other pharmaceutically acceptablecarriers and excipients, are also contemplated. As used herein, the termpharmaceutically acceptable carrier comprises such excipients, binders,lubricants, tabletting agents, disintegrants, preservatives,anti-oxidants, flavours and colourants as are typically used in the artof formulation of pharmaceuticals. Examples of such agents include—butare not limited to—starch, calcium carbonate, dibasic calcium phosphate,dicalcium phosphate, microcrystalline cellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose lactose, polyethylene glycols,polysorbates, glycols, safflower oil, sesame oil, soybean oil, andPovidone. Additionally, disintegrants such as sodium starch glycolate;lubricants such as magnesium stearate, stearic acid, and SiO₂; andsolubility enhancers such as cyclodextrins, among a great many otherexamples for each group, are contemplated. Such materials and themethods of using them are well known in the pharmaceutical art.Additional examples are provided in Kibbe, Handbook of PharmaceuticalExcipients, London, Pharmaceutical Press, 2000.

As used herein, the term “pharmaceutically acceptable acid salts” refersto acid addition salts formed from acids which provide non-toxic anions.The pharmaceutically acceptable anions include, but are not limited to,acetate, aspartate, benzoate, bicarbonate, carbonate, bisulfate,sulfate, chloride, bromide, benzene sulfonate, methyl sulfonate,phosphate, acid phosphate, lactate, maleate, malate, malonate, fumarate,lactate, tartrate, borate, camsylate, citrate, edisylate, esylate,formate, fumarate, gluceptate, glucuronate, gluconate oxalate,palmitate, pamoate, saccharate, stearate, suceinate, tartrate, tosylateand trifluoroacetate salts, among a great many other examples.Hemi-salts, including but not limited to hemi-sulfate salts, arelikewise contemplated.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

As is well known, pharmaceutically acceptable salts of compounds offormula I may be prepared by reaction of a compound of formula I withthe desired acid; by removal of a protecting group from a suitableprecursor of the compound of formula I or by ring-opening a suitablecyclic precursor, for example, a lactone or lactam, using the desiredacid or base; and by conversion of one salt of the compound of formula Ito another by reaction with an appropriate acid or base or by passagethrough an appropriate ion-exchange column.

As used herein, the term “pharmaceutically acceptable solvate” refers todescribe a molecular complex comprising the compound of the inventionand a stoichiometric amount of one or more pharmaceutically acceptablesolvent molecules, including but not limited to water and ethanol. Thus,the term solvate includes a hydrate as one example and an ethanolate asanother example.

As used herein, modulation of ion channels refers to activating the ionchannels, to affecting the kinetics of opening and closing of the ionchannels, or to causing any change in the channel open probability ofthe ion channels.

In some embodiments, the present invention provides a method of treatingor preventing a disease, disorder, or condition that is affected bymodulation of at least one potassium ion channel selected from KCNQ2/3,KCNQ4, and KCNQ5 in a patient comprising administration of a compound offormula IA-1. In such embodiments, KCNQ1 is substantially unaffected.Thus, compounds of formula IA-1 have been found to selectively affectmembers of the KCNQ-family of potassium channels associated with thenervous system, KCNQ2-5, while not affecting those associated withcardiac potential, KCNQ1. This selectivity is useful in the treatment ofdiseases, disorders, or conditions associated with the nervous systemwithout affecting the potassium channel KCNQ1 associated with the heart.Compounds of formula IA-1 can be used as antiepileptics,anticonvulsants, and in the treatment of neuropathic pain, for example.

In some embodiments, the present invention provides a method of treatingor preventing a disease, disorder, or condition that is affected bymodulation of at least one potassium ion channel selected from KCNQ2/3,KCNQ4, and KCNQ5 in a patient comprising administering compound A:

in an amount of from about 10 mg to about 2000 mg per day to a patient.In such embodiments, KCNQ1 is substantially unaffected. Thus, compound Ahas been found to selectively affect members of the KCNQ-family ofpotassium channels associated with the nervous system, KCNQ2-5, whilenot affecting those associated with cardiac potential, KCNQ1. Thisselectivity is useful in the treatment diseases, disorders, orconditions associated with the nervous system without affecting thepotassium channel KCNQ1 associated with the heart. Compound A can beused as antiepileptics, anticonvulsants, and in the treatment ofneuropathic pain, for example.

Preparation of Compounds General Strategy

Section I. The preparation of compounds of formula VI is outlined inScheme 1, in which, for convenience, a substitutedtetrahydroisoquinoline,

is symbolized by structure V.

Such substituted tetrahydroisoquinolines are either commerciallyavailable or are prepared from commercially available materials. A greatmany substituted tetrahydroisoquinolines are known, including many fusedisothiazole, piperidino and pyrrolidino derivatives. Thus, for example,compounds of formula IA where R₁ is 5-fluoro- can be prepared startingwith 5-fluoro-1,2,3,4-tetrahydroisoquinoline. Similarly, as anotheramong many examples, compounds of formula IA where R₁ or R₂ is 6-methylcan be prepared starting with 6-methyl-1,2,3,4-tetrahydroisoquinoline.and, again, in two more examples among many, compounds of formula IAwhere R₁ and R₂ are 6- and 7-chloro, respectively, can be preparedstarting with 6-, 7-dichloro-1,2,3,4-tetrahydroisoquinoline, andcompounds with a substituent in the 9-position can be prepared startingwith the appropriate 9-substituted tetrahydroisoquinoline. Analogously,compounds with R′ other than H can be prepared starting with theappropriate 1-, 3-, or 4-substituted tetrahydroisoquinolines. Forexamples, compounds in which, in the 1- and 4-positions, R′ is phenyl,methoxy, ethyl, methyl, F, or 2-(N-,N-dimethylamino)ethyl are accessiblevia the commercially available 1- and 4-substitutedtetrahydroisoquinolines.

In this procedure the aromatic amine I is brominated according tostandard procedures, including but not limited to the reaction with suchreagents as Nbromosuccinimide in an aprotic solvent such asacetonitrile. The reaction mixture is typically heated under reflux fora period of from approximately 8 to approximately 48 hours.

In a typical procedure, the resulting bromo derivative II is purified byfiltration of the crude reaction mixture through Celite. If desired,other standard purification techniques, including flash chromatography,can be used.

In the following step, the reaction of a compound II with theappropriate acyl chloride III in an aprotic solvent such as acetonitrileproduces the amide of general formula IV. This reaction is typicallyconducted at room temperature for a period of from approximately 4 toapproximately 48 hours. The resulting amide of general formula IV can bepurified by a standard chromatographic technique such as flashchromatography or thin layer chromatography.

The next step of the reaction sequence is to prepare the desired productof general Formula VI using the well-known palladium coupling reaction,employing a phosphine ligand such as the commercially availabledicyclohexyl phosphino-2′-(NN,-dimethylamino)biphenyl. Thus, the amineof general formula V can be coupled to the bromine derivative of generalformula IV using a palladium derivative such as, for example,bis(dibenzylidineacetone)palladium, a base such as potassiumtert-butoxide and the ligand dicyclohexyl phosphino-2′-(N,N,-dimethylamino)biphenyl in an aprotic solvent. The reaction mixture is typicallyheated in an oil bath at 90° C. for a period of from approximately 8 toapproximately 48 hours, or it can be heated using a microwave apparatus(Horizon unit, Biotage) at a temperature range of from approximately 90°to approximately 250° C. The desired compound of general formula VI ispurified by standard chromatographic techniques, such as flashchromatography or thin layer chromatography. It can also berecrystallized. from toluene.

Section II. The preparation of compounds of formula IX is outlined inScheme 2.

In reactions in section II, the compounds of general Formula IX areprepared in a way similar to that employed in section I. The anilinederivative II (section 1) is combined with the haloalkyl compound VIIunder standard conditions to produce the desired thioester of generalformula VIII. The reaction is typically conducted at a temperature offrom approximately 20° to approximately 90° C. for a period of fromapproximately 8 to approximately 48 hours, or in a microwave apparatus(Horizon unit, Biotage) at a temperature range of from approximately 90°to approximately 250° C. As in the previous sequence, the thioester canbe purified by standard chromatographic techniques such as flashchromatography or thin layer chromatography. The final step, a palladiumcoupling reaction to produce the compound of general Formula IX, isidentical to that described in the corresponding step in Section I.

Section III. The preparation of compound of formula XII is outlined inScheme 3.

In section III, the carbamate derivative of general Formula XI isobtained from the aniline derivative of general Formula TI (see sectionI) using standard conditions. Typically, the aniline is allowed to reactwith an anhydride derivative of general Formula X in the presence of abase such as triethyia:mine or diisopropyl ethylamine in an aproticsolvent such as methylene chloride. The reaction is conducted at atemperature in the range of from approximately −20° to approximately 40°C. for a period of from approximately 30 min to approximately 48 hours,depending on the particular substrates. The resulting carbamatederivative of general Formula XI can be purified by the usualchromatographic techniques, such as flash chromatography or thin layerchromatography. As in sections I and II, the final step is a palladiumcoupling.

Section IV. The preparation of compound of formula XIII is outlined inScheme 4.

Here, a compound of general Formula XII, obtained as in section III,reacts with Lawesson's reagent in an aprotic solvent such as methylenechloride to produce the thiocarbamate. Depending on the substratesinvolved, the reaction is stirred at room temperature or is heated underreflux for a period of from approximately 2 to approximately 48 hours.The resulting compound XIII can be purified by the usual chromatographictechniques, such as flash chromatography or thin layer chromatography.

Section V. The preparation of compound of formula XIV is outlined inScheme 5. Scheme 5:

The compound of general Formula XIV is obtained under the sameconditions described in section IV. The reaction is typically heatedunder reflux or stirred at room temperature for a period of fromapproximately 2 to approximately 48 hours. The resulting derivative ofgeneral Formula XIV can be purified by the usual chromatographictechniques, such as flash chromatography or thin layer chromatography.

Exemplary Compounds

Starting materials: bromodimethylaniline was obtained from either AlfaAesar or Sigma Aldrich.

Substituted tetrahydroisoquinolines commercially available; those usedin exemplary reactions here were obtained from ASW MedChem Inc., of NewBrunswick, N.J. Other substituted tetrahydroisoquinolines may besynthesized from commercially available starting materials via standardsynthetic techniques.

Example 1N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamideStep A: 4-bromo-2-chloro-6-(trifluoromethyl)aniline

N-bromo succinimide (910 mg, 5.1 mmol) was added to a solution of2-chloro-6-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) and acetic acid (3mL) in acetonitrile (10 mL) at room temperature. The mixture was heatedat reflux, with stirring, for 18 h. The reaction mixture was thenfiltered through Celite and concentrated to give the title compound,which was used in the next step without further purification.

Step B:N-(4-bromo-2-chloro-6-trifluoromethyl)phenyl-3,3-dimethylbutanamide

3,3-Dimethylbutanoyl chloride (1.08 g, 8.0 mmol) was added to a solutionof 4-bromo-2-chlor˜o-6-(trifluoromethyl)aniline (2.0 g, 7.3 mmol) inacetonitrile (10 mL). The reaction mixture was stirred at roomtemperature overnight. Water was added, and the mixture was thenextracted with ethyl acetate. The organic layer was dried over sodiumsulfate and concentrated. Purification by column chromatography indichloromethane afforded the title compound as a powder (1.22 g, 65%over the two steps).

Step C:N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.003 Smmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon), and thesolution was stirred for 15 minutes under argon. Potassium tert-butoxide(122 mg, 1.08 mmol), 1,2,3,4-tetrahydroisoquinoline (87 mg, 0.65 mmol),andN-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide(200 mg, 0.54 mmol) were then added, and the reaction mixture wasstirred at 90° C. overnight. The reaction mixture was then cooled toroom temperature, concentrated, and purified by thin layerchromatography (dichloromethane:methanol 5%) to afford the titlecompound as a solid. (106 mg, 47%). ¹H NMR (DMSO-d₆, 300 MHz) δ 1.02 (s,9H), 2.07 (s, 3H), 2.17 (s, 2H), 2.92 (t, J=5.4 Hz, 2H), 3.62(t, J=6 Hz,2H), 4.48 (s, 2H), 7.33 (m, 6H), 9.30 (s, 1H).

Example 2N-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-diumethylbutanamide Step A: N-(4-Bromo-2,6-dimethyl-phenyl)-33-dimethyl-butanamide

3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of4-bromo-2,6-dimethylphenylamine (5.0 g, 25 mmol) in acetonitrile (30mL). The reaction mixture was stirred at room temperature for 4 hours.Water was added to the mixture, and the precipitate which formed wascollected to give the title compound as a powder (7.46 g, 100%, yield).

Step B:N-(4-3,4-dihydroisoquinolin-2(1H)-2,6-dimethylphenyl)-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (150 mg, 1.34 mmol),1,2,3,4-tetrahydroisoquinoline (107 mg, 0.8 mmol) andN-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (200 mg, 0.67mmol) were then added, and the reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to room temperature,concentrated, and purified by thin layer chromatography(dichloromethane:methanol 5%) to afford the title compound as a solid.(113.20 mg, 50%).

¹H NMR (DMSO-d₆, 300 MHz) δ 1.03 (s, 9H), 2.08 (s, 6H), 2.15 (s, 2H),2.89 (t, J=5.7 Hz, 2H), 3.49 (t, J=5.7 Hz, 2H), 4.31 (s, 2H), 6.68 (s,2H), 7.2 (m, 4H), 8.86 (s, 1 H).

Example 3N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3-cyclopentylpropanamide Step A: 4-bromo-2-chloro-6-(trifluoromethyl)aniline

N-bromosuccinimide (910 mg, 5.1 mmol) was added to a solution of2-chloro-6-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) and acetic acid (3mL) in acetonitrile (10 mL) at room temperature. The mixture was stirredat reflux for 18 h. The reaction mixture was then filtered throughCelite and concentrated to give the title compound, which was used inthe next step without further purification.

Step B:N-(4-Bromo-2-chloro-6-trifluoromethyl-phenyl)-3-cyclopentyl-propionamide

3-Cyclopentyl propionyl chloride (1.28 g, 8.0 mmol) was added to asolution of 4-bromo-2-chloro-6-(trifluoromethyl)aniline (2.0 g, 7.3mmol) in acetonitrile (10 mL). The reaction mixture was stirred at roomtemperature overnight. Water was added, and the mixture was thenextracted with ethyl acetate. The organic layer was dried over sodiumsulfate and concentrated. Purification by column chromatography (100%DCM) afforded the title compound as a powder.

Step C:N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3-cyclopentylpropanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (150 mg, 1.34 mmol),1,2,3,4-tetrahydroisoquinoline (107 mg, 0.8 mmol), andN-(4-bromo-2-chloro-6-trifluoromethyl phenyl)-3-cyclopentyl propionamide(200 mg, 0.5 mmol) were then added, and the reaction mixture was stirredat 90° C. overnight. The reaction mixture was then cooled to roomtemperature, concentrated, and purified by thin layer chromatography(dichloromethane: methanol 5%) to afford the title compound as a solid.

Yield: 28%. ¹H NMR (CDCl₃, 300 MHz) δ 1.15 (m, 2H), 1.65 (m, 4H), 1.85(m, 4H), 2.44 (t, J=7.5 Hz, 2H), 3.01 (t, J=5.7. Hz, 2H), 3.6 (t, J=5.7.Hz, 2H), 4.43 (s, 2H), 6.72 (s, 1H), 7.10 (m, 2H), 7.24 (m, 4H).

Example 4N-(2-chloro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamideStep A: 6-fluoro-3,4-dihydroisoquinolin-1(2H)-one

Sodium azide (0.870 g, 13.33 mmol) was added in portions to a stirredsolution of 5-fluoro-1-indanone (1.0 g, 6.67 mmol) and methanesulfonicacid (4 mL) in dichloromethane (4 mL) at 0° C. The reaction mixture wasstirred at room temperature for 18 h. The mixture was then cooled to 0°C. and neutralized with 2N NaOH. The layers were separated, the aqueouslayer extracted with dichloromethane, and the combined organic layerswere dried over Na₂SO₄ and concentrated to give the title compound as awhite powder. The crude product was used in the next step.

Step B: 6-fluoro-1,2,3,4-tetrahydroisoquinoline

Diborane (1 M, THF, 24 mL) was added at 0° C. to a solution of6-fluoro-3,4-dihydro isoquinolin-1(2H)-one (1.14 g, 6.9 mmol) in THF (8mL). The mixture was stirred at reflux for 18 h. It was cooled to roomtemperature and water was added. The mixture was extracted withdichloromethane, and the organic layer was dried over sodium sulfate andconcentrated. Purification by column chromatography (hexanes:ethylacetate 1:1) afforded the title compound.

Step C:N-(2-chloro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-trifluoromethyl)phenyl-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl biphenyl-2-yl) dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (122 mg, 1.08 mmol),6-fluoato-1,2,3,4-tetrahydroisoquinoline (96 mg, 0.65 mmol), andN-(4-bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide(200 mg, 0.54 mmol) were then added, and the reaction mixture wasstirred at 90° C. overnight. The reaction mixture was then cooled toroom temperature, concentrated, and purified by thin layerchromatography (dichloromethane:methanol 5%) to afford the titlecompound as a solid. m/z=441 [M−1].

Example 5N-[2-Chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-phenyl]-3,3-dimethy-butanamideStep A: N-(4-Bromo-2-chloro-6-methylphenyl)-3,3-dimethyl butanamide

3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of4-bromo-2-chloro-6-methyl-phenylamine (5.0 g, 25 mmol) in acetonitrile(30 mL). The reaction mixture was stirred at room temperature for 4hours. Water was added to the mixture, and the precipitate that formedwas collected to give the title compound as a powder (7.46 g, 100%yield).

Step B:N-[2-Chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-phenyl-3,3-dimethyl-butanamide

The synthesis of this compound was performed as described in example 4,step C.

¹H NMR (DMSO-d₆, 300 MHz) δ 1.03 (s, 9H), 2.12 (s, 3H), 2.15 (s, 2H),2.89 (t, J=5.7 Hz, 2H), 3.53 (t, J=5.7 Hz, 2H), 4.36 (s, 2H), 6.87 (d,J=9.6, 2H), 7.2 (m, 4H), 9.08 (s, 1H).

Example 6N-[2-Chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl-phenyl)-3-cyclopentyl-propionamideStep A: 4-bromo-2-chloro-6-(trifluoromethyl)aniline

N-bromosuccinimide (910 mg, 5.1 mmol) was added at room temperature to asolution of 2-chloro-6-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) andacetic acid (3 mL) in acetonitrile (10 mL). The mixture was stirred atreflux to 18 h. The reaction mixture was then filtered through celiteand concentrated to give the title compound, which was used in the nextstep without further purification.

Step B: N-(4-Bromo-2-chloro-6-trifluoromethyl-phenyl)-3-cyclopentylpropionamide

3-Cyclopentyl propionyl chloride (1.28 g, 8.0 mmol) was added to asolution of 4-bromo-2-chloro-6-(trifluoromethyl)aniline (2.0 g, 7.3mmol) in acetonitrile (10 mL). The reaction mixture was stirred at roomtemperature overnight. Water was added to the mixture, which was thenextracted with ethyl acetate. The organic layer was dried over sodiumsulfate and concentrated. Purification by column chromatography (100%DCM) afforded the title compound as a powder.

Step C:N-[2-Chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl-phenyl]-3-cyclopentylpropionamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (140 mg, 1.25 mmol),6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (150 mg, 0.8mmol) andN-(4-Bromo-2-chloro-6-trifluoromethyl-phenyl)-3-cyclopentyl-propionamide(200 mg, 0.5 mmol) were then added and the reaction mixture was stirredat 90° C. overnight. The reaction mixture was then cooled to roomtemperature; concentrated, and purified by thin layer chromatography(dichloromethane:methanol 5%) to afford the title compound as a solid.

¹H NMR (DMSO-d₆, 300 MHz) δ 1.07 (m, 2H), 1.57 (m, 6H), 1.75 (m, 3H),2.31 (m, 2H), 2.93 (t, J=5.1 Hz, 2H), 3.60 (t, J=5.4 Hz, 2H), 4.45 (s,2H), 7.06 (m, 2H), 7.15 (s, 1H), 7.32 (m, 2H), 9.39 (s, 1H).

Example 7N-[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl-3,3-dimethylbutanamide Step A: N-(4-Bromo-26-dimethyl-phenyl-3,3-dimethyl-butanamide

3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of4-Bromo-2,6-dimethyl-phenylamine (5.0 g, 25 mmol) in acetonitrile (30mL). The reaction mixture was stirred at room temperature for 4 hours.Water was added to the mixture, and the precipitate which formed wascollected to give the title compound as a powder (7.46 g, 100% yield).

Step B:N-[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl-phenyl]-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0mmol) were added to dry toluene (150 mL purged with argon) and stirredfor 30 minutes under argon. Potassium tert-butoxide (4.75 mg, 42.3mmol), 6-Trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloridesalt (4.82 g, 20.3 mmol) andN-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g, 16.8 mmol)were then added, and the reaction mixture was stirred at 80° C.overnight. The reaction mixture was then cooled to room temperature andrecrystallized from toluene to afford the title compound as a solid.(5.55 g, 79%).

¹H NMR (DMSO-d6, 500 MHz) δ 1.03 (s, 9H), 2.09 (s, 6H), 2.15 (s, 2H),2.98 (t, J=5.0 Hz, 2H), 3.52 (t, J=6.0 Hz, 2H), 4.40 (s, 2H), 6.71 (s,2H), 7.45 (d, J=8.0, IH), 7.52 (m, 2H), 8.87 (s, 1H).

Example 8N-[2-Chloro-6-trifluoromethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide Step A: 4-bromo-2-chloro-6-(trifluoromethyl)aniline

N-bromosuccinimide (910 mg, 5.1 mmol) was added to a solution of2-chloro-6-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) in acetonitrile(10 mL) and acetic acid (3 mL) at room temperature. The mixture wasstirred at reflux to 18 h. The reaction mixture was then filteredthrough celite and concentrated to give the title compound which wasused in the next step without further purification.

Step B:N-(4-bromo-2-chloro-6(trifluoromethyl)phenyl)-3,3-dimethylbutanamide

3,3-dimethylbutanoyl chloride (1.08 g, 8.0 mmol) was added to a solutionof 4-bromo-2-chloro-6-(trifluoromethyl)aniline (2.0 g, 7.3 mmol) inacetonitrile (10 mL). The reaction mixture was stirred at roomtemperature overnight. Water was added to the mixture and then extractedwith ethyl acetate. The organic layer was dried over sodium sulfate andconcentrated. Purification by column chromatography (100% DCM) affordedthe title compound as a powder (1.22 g, 65%) over the two steps,

Step C:N-[2-Chloro-6-trifluoromethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-33-dimethyl butanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol),6-trifluoro-1,2,3,4-tetrahydroisoquinoline (154 mg, 0.65 mmol) andN-(4-bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide(200 mg, 0.54 mmol) were then added, and the reaction mixture wasstirred at 90° C. overnight. The reaction mixture was then cooled toroom temperature, concentrated, and purified by thin layerchromatography (dichloromethane:methanol 5%) to afford the titlecompound as a solid

¹H NMR (DMSO-d₆, 500 MHz) δ 1.03 (s, 9H), 2.17 (s, 2H), 3.02 (t, J=5.35Hz, 2H), 3.65 (t, J=5.0 Hz, 2H), 4.61 (s, 2H), 7.19 (d, J=2.0 Hz, 1H),7.38 (d, J=1.9 Hz, IH), 7,49 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H),7.59 (s, 1H), 9.32 (s, 1H).

Example 9N-[2-Chloro-4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl-phenyl]-3,3-dimethylbutanamide Step A: 4-bromo-2-chloro-6-(trifluoromethyl)aniline

N-bromosuccinimide (910 mg, 5.1 mmol) was added to a solution of2-chloro-6-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) in acetonitrile(10 mL) and acetic acid (3 mL) at room temperature. The mixture wasstirred at reflux to 18 h. The reaction mixture was then filteredthrough Celite and concentrated to give the title compound which wasused in the next step without further purification.

Step B:N-(4-bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3dimethylbutanamide

3,3-Dimethylbutanoyl chloride (1.08 g, 8.0 mmol) was added to a solutionof 4-bromo-2-chloro-6-(trifluoromethyl)aniline (2.0 g, 7.3 mmol) inacetonitrile (10 mL). The reaction mixture was stirred at roomtemperature overnight. Water was added to the mixture and then extractedwith ethyl acetate. The organic layer was dried over sodium sulfate andconcentrated. Purification by column chromatography (100% DCM) affordedthe title compound as a powder (1.22 g, 65%) over the two steps.

Step C:N-[2-Chloro-4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl-phenyl]-3,3-dimethyl-butanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (151 mg, 1.35 mmol),6-chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (133 mg, 0.65mmol) andN-(4-bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide(200 mg, 0.54 mmol) were then added and the reaction mixture was stirredat 90° C. overnight. The reaction mixture was then cooled to roomtemperature, concentrated and purified by thin layer chromatography(dichloromethane:methanol 5%) to afford the title compound as a solid.

¹H NMR (DMSO-d₆, 500 MHz) δ 1.02 (s, 9H), 2.17 (s, 2H), 2.92 (t, J=5.35Hz, 2H), 3.61 (t, J=5.6 Hz, 2H), 4.47 (s, 2H), 7.16 (s, IH), 7.29 (m,3H), 7.34 (s, IH), 9.31(s, IH).

Example 10N-[4-(6-Chloro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl-3,3-dimethylbutanamideStep A: N-(4-Bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide

3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of4-bromo-2,6-dimethyl phenylamine (5.0 g, 25 mmol) in acetonitrile (30mL). The reaction mixture was stirred at room temperature for 4 hours.Water was added to the mixture and the precipitate formed collected togive the title compound as a powder (7.46 g, 100% yield).

Step B:N-[4-(6-Chloro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (5 mL purged with argon) and stirred for15 minutes under argon. Potassium tert-butoxide (188 mg, 1.7 mmol),6-chloro-1,2,3,4-tetrahydro isoquinoline hydrochloride salt (165 mg, 0.8mmol), and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (200mg, 0.67 mmol) were then added, and the reaction mixture was stirred at80° C. overnight. The reaction mixture was then cooled to roomtemperature and filtered through silica gel. Purification by preparativethin layer chromatography afforded the title compound as a solid.

¹H NMR (DMSO-d₆, 500 MHz) δ 1.03 (s, 9H), 2.08 (s, 6H), 2.15 (s, 2H),2.89 (t, J=5.25 Hz, 2H), 3.47 (t, J=5.6 Hz, 2H), 4.30 (s, 2H), 6.68 (s,2H), 7.25 (m, 3H), 8.85 (s, 11-1).

Example 11 N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethyl butanamide Step A:N-(4-Bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide

3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of4-bromo-2,6-dimethylphenylamine (5.0 g, 25 mmol) in acetonitrile (30mL). The reaction mixture was stirred at room temperature for 4 hours.Water was added to the mixture, and the precipitate which formed wascollected to give the title compound as a powder (7.46 g, 100% yield).

Step B:N-[4-(6-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0mmol) were added to dry toluene (150 mL purged with argon for 30minutes) and stirred for 30 minutes under argon. Potassium tert-butoxide(4.75 mg, 42.3 mmol), 6-fluoro-1,2,3,4-tetrahydro-isoquinolinehydrochloride salt (3.2 g, 17.0 mmol), andN-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g, 16.8 mmol)were then added, and the reaction mixture was stirred at 80° C.overnight. The reaction mixture was then cooled to room temperature andrecrystallized from toluene to afford the title compound as a solid.(5.11 g, 83%).

¹H NMR (DMSO-d₆, 500 MHz) δ 1.03 (s, 9H), 2.08 (s, 6H), 2.15 (s, 2H),2.89 (t, J=5.25 Hz, 2H), 3.47 (t, J=5.6 Hz, 2H), 4.30 (s, 2H), 6.68 (s,2H), 6.99 (m, 2H), 7.25 (m, 1H), 8.84 (s, 1H).

Example 12N-[2-Chloro-4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl-phenyl]-3,3-dimethylbutanamideStep A: 4,bromo-2-chloro-6-(trifluoromethyl)aniline

N-bromosuccinimide (910 mg, 5.1 mmol) was added to a solution of2-chloro-6-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) in acetonitrile(10 mL) and acetic acid (3 mL) at room temperature. The mixture wasstirred at reflux for 18 h. The reaction mixture was then filteredthrough Celite and concentrated to give the title compound, which wasused in the next step without further purification.

Step B:N-(4-bromo-2-chloro-6-trifluoromethyl)phenyl-3,3-dimethylbutanamide

3,3-Dimethylbutanoyl chloride (1.08 g, 8.0 mmol) was added to a solutionof 4 bromo-2-chloro-6-(trifluoromethyl)aniline (2.0 g, 7.3 mmol) inacetonitrile (10 mL). The reaction mixture was stirred at roomtemperature overnight. Water was added to the mixture and then extractedwith ethyl acetate. The organic layer was dried over sodium sulfate andconcentrated. Purification by column chromatography (100% DCM) affordedthe title compound as a powder (1.22 g, 65%) over the two steps.

Step C:N-[2-Chloro-4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl-phenyl]-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (151 mg, 1.35 mmol),7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (122 mg, 0.65mmol) andN-(4-bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide(200 mg, 0.54 mmol) were then added, and the reaction mixture wasstirred at 90° C. overnight. The reaction mixture was then cooled toroom temperature, concentrated, and purified by thin layerchromatography (dichloromethane:methanol 5%) to afford the titlecompound as a solid.

¹H NMR (DMSO-d₆, 500 MHz) δ 1.02 (s, 9H), 2.17 (s, 2H), 2.89 (t, J=5.1Hz, 2H), 3.61 (t, J=5.7 Hz, 2H), 4.49 (s, 2H), 7.03 (dd, J=8.6, 2.3 Hz,1H), 7.12 (m, 2H), 7.16 (d, J=2.2 Hz, 1H), 7.23 (m, 1H), 7.33 (d, J=2.6,1H), 9.30 (s, 1H).

Example 13N-[4-(7-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dimethyl-butanamideStep A: N-(4-Bromo-2,6-dimethyl-phenyl-3,3-dimethyl-butanamide

3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of4-Bromo-2,6-dimethyl-phenylamine (5.0 g, 25 mmol) in acetonitrile (30mL). The reaction mixture was stirred at room temperature for 4 hours.Water was added to the mixture and the precipitate formed collected togive the title compound as a powder (7.46 g, 100% yield).

Step B:N-[4-(7-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl-3,3-dimethyl-butanamide

Bis(dibenzylidineacetone)palladium (156 mg, 0.28 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (320 mg, 0.8mmol) were added to dry toluene (60 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (1.9 g, 16.25 mmol),7-fluoro-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (1.28 g, 6.8mmol), and N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g,6.8 mmol) were then added, and the reaction mixture was stirred at 80°C. overnight. The reaction mixture was then cooled to room temperatureand recrystallized from toluene to afford the title compound as a solid.(1.9 g, 76%).

¹H NMR (DMBO-d₆, 400 MHz) δ 1.05 (s, 9H), 2.10 (s, 6H), 2.17 (s, 2H),2.89 (t, J=5.1 Hz, 2H), 3.49 (t, J=5.7 Hz, 2H), 4.34 (s, 2H), 6.70 (s,2H), 7.0 (m, IH), 7.1 (m, 1H), 7.2 (m, 1H), 8.9 (s, 1H).

Example 14N-[2-Chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamideStep A: N-(4-Bromo-2-chloro-6-methyl-phenyl-3 3-dimethyl-butanamide

3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of4-Bromo-2-chloro-6-methylphenylamine (5.0 g, 25 mmol) in acetonitrile(30 mL). The reaction mixture was stirred at room temperature for 4hours. Water was added to the mixture and the precipitate formedcollected to give the title compound as a powder (7.46 g, 100% yield).

Step B:N-[2-Chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol),6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (121 mg, 0.65mmol) and N-(4-bromo-2-chloro-6-methylphenyl)-3,3-dimethylbutanamide(200 mg, 0.63 mmol) were then added and the reaction mixture was stirredat 90° C. overnight. The reaction mixture was then cooled to roomtemperature, concentrated and purified by thin layer chromatography(dichloromethane:methanol 5%) to afford the title compound as a solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 1.05 (s, 9H), 2.14 (s, 3H), 2.17 (s, 2H),2.91 (t, J=5.25 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.37 (s, 2H), 6.85 (s,IH), 6.9 (s, 1H), 7.0 (m, 2H), 7.3 (m, 1H), 9.10 (s, 1H).

Example 15N-[2-Chloro-4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamideStep A: N-(4-Bromo-2-chloro-6-methyl-phenyl-3,3-dimethyl-butanamide

3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of4-Bromo-2-chloro-6-methyl-phenylamine (5.0 g, 25 mmol) in acetonitrile(30 mL). The reaction mixture was stirred at room temperature for 4hours. Water was added to the mixture and the precipitate formedcollected to give the title compound as a powder (7.46 g, 100% yield).

Step B:N-[2-Chloro-4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol),7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (121 mg, 0.65mmol) and N-(4-bromo-2-chloro-6-methylphenyl)-3,3-dimethylbutanamide(200 mg, 0.63 mmol) were then added and the reaction mixture was stirredat 90° C. overnight. The reaction mixture was then cooled to roomtemperature, concentrated, and purified by thin layer chromatography(dichloromethane:methanol 5%) to afford the title compound as a solid.

¹H NMR (DMSQ-d₆, 400 MHz) δ 1.04 (s, 9H), 2.14 (s, 3H), 2.18 (s, 2H),2.88 (t, J=5.25 Hz, 2ff), 3.55 (t, J=5.6 Hz, 2H), 4.4 (s, 2H), 6.88 (s,1H), 6.9 (s, 1H), 7.0 (m, 1H), 7.1 (m, 1H), 7.2 (m, 1H), 9.10 (s, 1H).

Example 16N-[2-Chloro-6-methyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamideStep A: N-(4-Bromo-2-chloro-6-methyl-phenyl-3,3-dimethyl-butanamide

3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution. of4-Bromo-2-chloro-6-methylphenylamine (5.0 g, 25 mmol) in acetonitrile(30 mL). The reaction mixture was stirred at room temperature for 4hours. Water was added to the mixture and the precipitate formedcollected to give the title compound as a powder (7.46 g, 100% yield).

Step B:N-[2-Chloro-6-methyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol),6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (154mg, 0.65 mmol) andN-(4-bromo-2-chloro-6-methylphenyl)-3,3-dimethylbutanamide (200 mg, 0.63mmol) were then added and the reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to room temperature,concentrated and purified by thin layer chromatography(dichloromethane:methanol 5%) to afford the title compound as a solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 1.08 (s, 9H), 2.17(s, 3H), 2.21 (s, 2H), 3.0(t, J=5.25 Hz, 2H), 3.6 (t, J=5.6 Hz, 2H), 4.5 (s, 2H), 6.9 (s, 1H),6.95 (s, 1H), 7.3 (m, 1H), 7.5 (m, 2H), 9.13 (s, 1H).

Example 17N-[2-Chloro-4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-phenyl]-3,3-dimethylbutanamideStep A: N-(4-Bromo-2-chloro-6-methyl-phenyl-3,3-dimethylbutanamide

3,3-dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of4-Bromo-2-chloro-6-methyl-phenylamine (5.0 g, 25 mmol) in acetonitrile(30 mL). The reaction mixture was stirred at room temperature for 4hours. Water was added to the mixture and the precipitate formedcollected to give the title compound as a powder (7.46 g, 100% yield).

Step:N-2-Chloro-4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-phenyl]-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-di.methylamine (3.3 mg,0.0084 mmol) were added to dry toluene (10 mL purged with argon) andstirred for 15 minutes under argon. Potassium tert-butoxide (197 mg,1.75 mmol), 6-chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt(133 mg, 0.65 mmol), andN-(4-bromo-2-chloro-6-methylphenyl)-3,3-dimethylbutanamide (200 mg, 0.63mmol) were then added, and the reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to room temperature,concentrated, and purified by thin layer chromatography(dichloromethane:methanol 5%) to afford the title compound as a solid.

¹H NMR (DMS4-d₆, 400 MHz) δ 1.06 (s, 9H), 2.14 (s, 3H), 2.18 (s, 2H),2.9 (t, J=5.25 Hz, 2H), 3.5 (t, J=5.6 Hz, 2H), 4.4 (s, 2H), 6.85 (s,1H), 6.9 (s, 1H), 7.25 (m, 3H), 9.1 (s, 1H).

Example 18N-[2-Chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamideStep A: N-(4-Bromo-2-chloro-phenyl-3,3-dimethyl-butanamide

3,3-Dimethylbutanoyl chloride (717 mg, 0.74 mL, 5.32 mmol) was added toa solution of 4-Bromo-2-chloro-phenylamine (1.0 g, 4.84 mmol) inacetonitrile (10 mL). The reaction mixture was stirred at roomtemperature overnight. Water was added to the mixture and theprecipitate formed collected to give the title compound as a powder(1.04 g, 72% yield).

Step B:N-[2-Chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl-3,3-dimethylbutanamide

¹H NMR (DMSO-d₆, 400 MHz) δ 1.04 (s, 9H), 2.19 (s, 2H), 2.93 (t, J=8 Hz,2H), 3.54 (t, J=8 Hz, 2H), 4.37 (s, 2H), 6.96 (dd, J=4, 12 Hz, 1H), 7.04(m, 3H), 7.27 (m, 1H), 7.34 (d, J=8 Hz, 1H), 9.17 (s, 1H).

Example 19N-[4-(6-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-phenyl]-3,3-dimethylbutanamideStep A: N-(4-Bromo-2-methyl-phenyl-3,3-dimethylbutanamide

3,3-Dimethylbutanoyl chloride (724 mg, 0.75 mL, 5.4 mmol) was added to asolution of 4-Bromo-2-methyl-phenylamine (1.0 g, 5.4 mmol) inacetonitrile (10 mL). The reaction mixture was stirred at roomtemperature overnight. Water was added to the mixture and theprecipitate formed collected to give the title compound as a powder (830mg, 56% yield).

Step B:N-[4-(6-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-phenyl-3,3-dimethylbutanamide

The synthesis of this compound was performed as described in example 4,step C.

1H NMR (DMSO-d₆, 400 MHz) δ 1.04 (s, 9H), 2.14 (s, 3H), 2.16 (s, 2H),2.91 (t, J=8 Hz, 2H), 3.48 (t, J=8 Hz, 2H), 4.31 (s, 2H), 6.8 (dd, J=4,12 Hz, 1H), 6.85 (s, 1H), 7.0 (m, 2H), 7.09 (d, J=8 Hz, 1H), 7.3 (m,1H), 8.98 (s, 1H).

Example 20N-[4-(6-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-trifluoromethylphenyl]-3,3-dimethylbutanamideStep A: N-(4-Bromo-2-trifluoromethyl-phenyl-3,3-dimethylbutanamide

3,3-Dimethylbutanoyl chloride (617 mg, 0.64 mL, 4.6 mmol) was added to asolution of 4-Bromo-2-trifluoromethyl-phenylamine (1.0 g, 4.16 mmol) inacetonitrile (10 mL). The reaction mixture was stirred at roomtemperature overnight. Water was added to the mixture and theprecipitate formed collected to give the title compound as a powder (1.1g, 79% yield).

Step B:N-[4-(6-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl-2-trifluoromethyl-phenyl-3,3-dimethylbutanamide

The synthesis of this compound was performed as described in example 4,step C.

¹H NMR (DMSO-d₆, 400 MHz) δ 1.02 (s, 9H), 2.18 (s, 2H), 2.94 (t, J=8 Hz,2H), 3.59 (t, J=8 Hz, 2H), 4.43 (s, 2H), 7.0 (m, 2H), 7.17 (m, 3H), 7.3(m, 1H), 9.18 (s, 1H).

Example 21N-[2-Chloro-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamideStep A: N-(4-Bromo-2-chloro-phenyl)-3,3-dimethylbutanamide

3,3-Dimethylbutanoyl chloride (717 mg, 0.74 mL, 5.32 mmol) was added toa solution of 4-Bromo-2-chloro-phenylamine (1.0 g, 4.84 mmol) inacetonitrile (10 mL). The reaction mixture was stirred at roomtemperature overnight. Water was added to the mixture and theprecipitate formed collected to give the title compound as a powder(1.04 g, 72% yield).

Step B:N-[2-Chloro-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol),6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (154mg, 0.65 mmol) and N-(4-bromo-2-chloro)-3,3-dimethylbutanamide (200 mg,0.66 mmol) were then added and the reaction mixture was stirred at 90°C. overnight. The reaction mixture was then cooled to room temperature,concentrated, and purified by thin layer chromatography(dichloromethane:methanol 5%) to afford the title compound as a solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 1.03 (s, 9H), 2.19 (s, 2H), 2.99 (t, J=8 Hz,2H), 3.58 (t, J=8 Hz, 2H), 4.48 (s, 2H), 6.99 (dd, J=4, 8 Hz, 1H), 7.08(d, J=4 Hz, 1H), 7.35 (dd, J=4, 8 Hz, 1H), 7.48 (dd, J=4, 8 Hz, 1H),7.56 (m, 2H), 9.19 (s, 1H).

Example 22N-[4-(7-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-trifluoromethyl-phenyl]-3,3-dimethylbutanamideStep A: N-(4-Bromo-2-trifluoromethyl-phenyl-3,3-dimethyl-butanamide

3,3-Dimethylbutanoyl chloride (617 mg, 0.64 mL, 4.6 mmol) was added to asolution of 4-Bromo-2-trifluoromethyl-phenylamine (1.0 g, 4.16 mmol) inacetonitrile (10 mL). The reaction mixture was stirred at roomtemperature overnight. Water was added to the mixture and theprecipitate formed collected to give the title compound as a powder (1.1g, 79% yield).

Step B:[N-4-(7-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-trifluoromethyl-phenyl-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mm.ol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol),7-Fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (122 mg, 0.65mmol) and N-(4-bromo-2-trifluoromethyl)-3,3-dimethylbutanamide (200 mg,0.59 mmol) were then added and the reaction mixture was stirred at 90°C. overnight. The reaction mixture was then cooled to room temperature,concentrated and purified by thin layer chromatography (dichloromethane100%) to afford the title compound as a solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 1.02 (s, 911), 2.18 (s, 2H), 2.90 (t, J 8Hz, 2H), 3.60 (t, J=8 Hz, 2H), 4.46 (s, 2H), 7.0 (m, 1H), 7.23 (m, 5H),9.17(s, 1H).

Example 233,3-Dimethyl-N-[2-trifluoromethyl-4-(7-trifluoromethyl-3,4-dihydro-1H-isoquinolin2-yl)-phenyl]-butanamideStep A: N-(4-Bromo-2-trifluoromethyl-phenyl)-3,3-dimethylbutanamide

3,3-Dimethylbutanoyl chloride (617 mg, 0.64 mL, 4.6 mmol) was added to asolution of 4-Bromo-2-trifluoromethyl-phenylamine (1.0 g, 4.16 mmol) inacetonitrile (10 mL). The reaction mixture was stirred at roomtemperature overnight. Water was added to the mixture and theprecipitate formed collected to give the title compound as a powder (1.1g, 79% yield).

Step B:3,3-Dimethyl-N-2-trifluoromethyl-4-(7-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]butanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol),7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (154mg, 0.65 mmol) and N-(4-bromo-2-trifluoromethyl)-3,3-dimethylbutanamide(200 mg, 0.59 mmol) were then added and the reaction mixture was stirredat 90° C. overnight. The reaction mixture was then cooled to roomtemperature, concentrated and purified by thin layer chromatography(Dichloromethane 100%) to afford the title compound as a solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 1.02 (s, 9H), 2.18 (s, 2H), 3.01 (t, J=8 Hz,2H), 3.62 (t, J=8 Hz, 2H), 4.56 (s, 2H), 7.24 (m, 3H), 7.44 (d, J=4 Hz,1H), 7.52 (d, J=4 Hz, 1H), 7.67 (s, 1H), 9.18 (s, 1H).

Example 24N-[4-(6-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dimethylbutanamide Step A:N-(4-Bromo-2,6-dimethyl-phenyl-3,3-dimethyl-butanamide

3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of4-Bromo-2,6-dimethyl-phenylamine (5.0 g, 25 mmol) in acetonitrile (30mL). The reaction mixture was stirred at room temperature for 4 hours.Water was added to the mixture and the precipitate formed collected togive the title compound as a powder (7.46 g, 100% yield).

Step B: N-[4-(6-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-26-dimethyl-phenyl]-3,3-dimethylbutanamide

Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084mmol) were added to dry toluene (10 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol),6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (134 mg,0.67 mmol) and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide(200 mg, 0.67 mmol) were then. added and the reaction mixture wasstirred at 80° C. overnight. The reaction mixture was then cooled toroom temperature, concentrated, filtered through a pad of silica gel,and recrystallized from toluene to afford the title compound as a solid.

¹H NMR (DMS4-d₆, 400 MHz) δ 1.05 (s, 9H), 2.10 (s, 6H), 2.14 (s, 2H),2.87 (t, J=8 Hz, 2H), 3.48 (t, J=8 Hz, 2H), 3.72 (s, 3H), 4.26 (s, 2H),6.68 (s, 2H), 6.79 (m, 2H), 7.14 (m, 1H), 8.85 (s, 1H).

Example 25N-[2,6-Dimethyl-4-(7-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide Step A: N-(4-Bromo-2,6-dimethyl-phenyl-3,3-dimethylbutanamide

3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of4-bromo-2,6-dimethyl-phenylamine (5.0 g, 25 mmol) in acetonitrile (30mL). The reaction mixture was stirred at room temperature for 4 hours.Water was added to the mixture, and the precipitate that formed wascollected to give the title compound as a powder (7.46 g, 100% yield).

Step B:N-[2,6-Dimethyl-4-(7-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl-butanamide

Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and(2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0mmol) were added to dry toluene (150 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (4.75 g, 42.3 mmol),7-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt(4.82 g, 20.3 mmol) andN-(4-Bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g, 16.8 mmol)were then added and the reaction mixture was stirred at 80° C.overnight. The reaction mixture was then cooled to room temperature,filtered through silica gel, and recrystallized from toluene to affordthe title compound as a solid. (5.94 g, 85%).

¹H NMR (DMSO-d₆, 400 MHz) δ 1.06 (s, 9H), 2.11 (s, 6H), 2.18 (s, 2H),2.89 (t, J=4 Hz, 2H), 3.54 (t, J=4 Hz, 2H), 4.44 (s, 2H), 6.73 (s, 2H),7.40 (d, J=8 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 7.62 (s, 1H), 8.87 (s, 1H).

Example 26N-[4-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-methoxy-6-methyl-phenyl]-3,3-dimethyl-butanamideStep A: 4-bromo-2-methoxy-6-methyl-aniline

To an ice-water cooled solution of 2-methoxy-6-methylaniline (10 g, 72.9mmol) in 30 mL of methanol and 10 mL of acetic acid was added dropwisebromine (3.75 mL, 72.9 mmol). The reaction mixture was allowed to standfor overnight. The solvent was removed under reduced pressure and theresidue was suspended in 60 mL of IN NaOH and extracted with ethylacetate and dried over sodium sulfate and evaporated to dryness to givereddish crude product, which was recrystallized from hexane to give pureproduct (14.3 g, 91%).

Step B: 4-Bromo-2-methoxy-6-methyl-phenyl-3,3-dimethyl butanamide

To a solution of 4-bromo-2-methoxy-6-methyl-aniline (2.2 g, 10 mmol) andtriethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane (50 mL) wasadded dropwise tert-butylacetyl chloride (1.6 g, 12 mmol) with stirringat room temperature. The reaction mixture was stirred for 3 hours atroom temperature, than the reaction mixture was diluted withdichloromethane and washed with water and dried over anhydrous sodiumsulfate and evaporated to dryness under reduced pressure. The residuewas purified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) togive a white solid (2.8 g, 89%).

Step C:N-[4-3,4-Dihydro-1H-isoquinolin-2-yl)-2-methoxy-6-methyl-phenyl]-3,3-dimethyl-butanamide

Toluene (6 ml) was degassed with nitrogen for 15 min in a 10 mL ofmicrowave tube, then(4-bromo-2-methoxy-6-methyl-phenyl)-3,3-dimethyl-butanamide (188 mg, 0.6mmol) and 1,2,3,4-tetrahydroisoquinoline (96 mg, 0.72 mmol) was added,followed by potassium tert-butoxide (101 mg, 0.9 mmol),bis(dibenzylidene acetone)palladium (17 mg, 0.03 mmol), and2-dicyclohexyphosphino-2-(N,N-dimethylamino)biphenyl (24 mg, 0.06 mmol).The reaction tube was sealed and reacted in microwave at 100° C. for 2hours. The reaction mixture was purified by silica gel column (ISCO,hexane/EtOAc, 0-40%, 40 min) to give pure compound as a white solid.

¹H-NMR (DMSO-d₆, 400 MHz): δ 8.64 (brs, 1H, exchangeable with D₂0), 7.20(m, 4H), 6.48 (s, 1H), 6.43 (s, 1H), 4.37 (s, 2H), 3.73 (s, 3H), 3.52(t, J=6.OHz, 2H), 2.92 (t, J=6.OHz, 2H), 2.13 (s, 2H), 2.08 (S, 3H),1.04 (s, 9H). MS: 367 (M+1).

Example 27N-[2-Chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethoxy-phenyl]-3,3-dimethyl-butanamideStep A:N-(4-Bromo-2-chloro-6-trifluoromethoxy-phenyl-3,3-dimethyl-butanamide

To a solution of 4-bromo-2-chloro-6-trifluoromethoxy-aniline (2.9 g, 10mmol) and triethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane(50 mL) was added dropwise tert-butylacetyl chloride (1.6 g, 12 mmol)with stirring at room temperature. The reaction mixture was stirred for3 hours at room temperature, than the reaction mixture was diluted withdichloromethane and washed with water and dried over anhydrous sodiumsulfate and evaporated to dryness under reduced pressure. The residuewas purified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) togive a white solid (3.6 g, 93%).

Step B:N-[2-Chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl-6-trifluoromethoxy-phenyl]-3,3-dimethylbutanamide

Synthesized according to example 26: ¹H-NMR (DMSO-d₆, 400 MHz): δ 9.28(brs, 1H, exchangeable with D₂O), 7.20 (m, 4H), 7.10 (s, I H), 6.89 (s,1H), 4.45 (s, 2H), 3.57 (t, J=6.0 Hz, 2H), 2.92 (t, J=6.0 Hz, 2H), 2.18(s, 2H), 1.04 (s, 9H). MS: 441 (M+1),

Example 28N-[4-(3,4-Dihydro-1H-isoquinolin-2-yl)-2,6-dimethoxy-phenyl]-3,3-dimethyl-butanamideStep A: 5-Bromo-1,3-dimethoxy-2-nitro-benzene

1-Bromo-3,5-dimethoxybenzene (10.9 g, 50 mmol) was dissolved in 100 mLof acetic anhydride and cooled to 0° C. A cooled solution of 70% HNO₃(6.4 mL, 100 mmol) in 20 mL of acetic anhydride was added dropwise andthe resulting mixture was stirred for 1 hour at 0° C. and for 3 hours atroom temperature. The reaction mixture was poured into ice-water withstrong stirring and the yellow solid was filtered and washed with water.The solid as a mixture of two isomers was separated by silica gel column(ISCO, hexane/EtOAc, 0-30%, 40 min) to give 3.3 g(25%) of pure5-bromo-1,3-dimethoxy-2-nitro-benzene as an yellow solid. ¹H-NMR(DMSO-d₆, 400 MHz): δ 7.17 (s, 2H), 3.89 (s, 6H).

Step B: 5-Bromo-1,3-dimethoxy-2-amino-benzene

5-Bromo-1,3-dimethoxy-2-nitro-benzene (2.6 g, 10 mmol) was dissolved in200 mL of methanol and 40 mL of water was added, followed by 2.5 g of Fepowder and 2.5 g of ammonium chloride. The mixture was heated to refluxat 80° C. for 2 hours and the cooled reaction mixture was filtered andwashed with methanol. The filtrate was evaporated under reduce pressureto give the crude product, which was used for next step without furtherpurification.

Step C: N-(4-Bromo-2,6-dimethoxy-phenyl-3,3-dimethyl-butanamide

To a solution of the crude 5-bromo-1,3-dimethoxy-2-amino-benzene fromabove and triethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane(50 mL) was added dropwise tert-butyl acetyl chloride (1.6 g, 12 mmol)with stirring at room temperature. The reaction mixture was stirred for3 hours at room temperature. Then the reaction mixture was diluted withdichloromethane, washed with water, dried over anhydrous sodium sulfate,and evaporated to dryness under reduced pressure. The residue waspurified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) togive a white solid (3.0 g, 91%). ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.69 (brs,1H, exchangeable with D₂0), 6.87 (s, 2H), 3.73 (s, 6H), 2.11 (s, 2H),1.02 (s, 9H).

Step D:N-[4-(3,4-Dihydro-1H-isoquinolin-2-yl)-2,6-dimethoxy-phenyl-3,3-dimethyl-butanamide

Toluene (6 mL) was degassed with nitrogen for 15 min in a 10 mL ofmicrowave tube, then N-(4-bromo-2,6-dimethoxy phenyl)-3,3-dimethylbutanamide (200 mg, 0.6 mmol) and 1,2,3,4-tetrahydroisoquinoline (96 mg,0.72 mmol) was added, followed by potassium tert-butoxide (101 mg, 0.9mmol), bis(dibenzylidene acetone)palladium (17 mg, 0.03 mmol), and2-dicyclohexyphosphino-2-(N,N-dimethylamino)biphenyl (24 mg, 0.06 mmol).The reaction tube was sealed and reacted in microwave at 100° C. for 2hours. The reaction mixture was purified by silica gel column (ISCO,hexane/EtOAc, 0-40%, 40 min) to give pure compound as a white solid.¹H-NMR (DMSO-d₆, 400 MHz): δ 8.36 (brs, 1H, exchangeable with D₂O), 7.20(m, 4H), 6.25 (s, 2H), 4.41 (s, 2H), 3.72 (s, 6H), 3.55 (t, J=6.OHz,2H), 2.95 (t, J=6.OHz, 2H), 2.07 (s, 2H), 1,03 (s, 9H). MS: 383 (M+1).

Example 28N-[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl-thiobutanamideStep A: N-(4-Bromo-2,6-dimethyl-phenyl-3,3-dimethyl-butyramide

3,3-dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) andtriethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of4-Bromo-2,6-dimethyl-phenylamine (5.0 g, 25 mmol) in acetonitrile (30mL). The reaction mixture was stirred at room temperature for 4 hours.Water was added to the mixture and the precipitate formed collected togive the title compound as a powder (7.46 g, 100% yield).

Step B:N-[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl-butanamide

Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and(2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0mmol) were added to dry toluene (150 mL purged with argon) and stirredfor 15 minutes under argon. Potassium tert-butoxide (4.75 mg, 42.3mmol), 6-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline hydrochloridesalt (4.82 g, 20.3 mmol) andN-(4-Bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butyramide (5 g, 16.8 mmol)were then added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature andrecrystallized from toluene to afford the title compound as a solid.(5.55 g, 79%).

₁H NMR (DMSO-d₆, 500 MHz) δ 1.03 (s, 9H), 2.09 (s, 6H), 2.15 (s, 2H),2.98 (t, J=5.0 Hz, 2H), 3.52 (t, J=6.0 Hz, 2H), 4.40 (s, 2H), 6.71 (s,2H), 7.45 (d, J=8.0, 1H), 7.52 (m, 2H), 8.87 (s, 1H).

Step C:N-[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl-phenyl]-3,3-dimethyl-thiobutanamide

To a solution ofN-[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl-butyramide(200 mg, 0.48 mmol) in dichloroethane (10 mL) was added Lawesson'sreagent (193 mg, 0.48 mmol) and the reaction mixture was stirred atreflux for 2 h. The mixture was then cooled to room temperature andconcentrate. Purification by preparative thin layer chromatography(dichloromethane 100%) afforded the desired compound as a solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 1.12 (s, 9H), 2.11 (s, 6H), 2.73 (s, 2H),3.0 (t, J=5.0 Hz, 2H), 3.57 (t, J=4.0 Hz, 2H), 4.46 (s, 2H), 6.75 (s,2H), 7.47 (d, J=8.0, IH), 7.56 (m, 2H), 10.7 (s, 1H).

Example 29[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-carbamicacid ethyl ester Step A: (4-Bromo-2,6-dimethyl-phenyl-carbamic acidethyl ester

Ethyl chloroformate (0.55 g, 0.48 mL, 5 mmol) was added to a solution of4-bromo-2,6-dimethyl-phenylamine (1.0 g, 5 mmol) in acetonitrile (20mL). The reaction mixture was stirred at reflux for 16 hours. Water wasadded to the mixture and the precipitate formed collected to give thetitle compound as a powder (1.32 g, 97% yield).

Step B:[2,6-Dimethyl-4-6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl-phenyl]-carbamicacid ethyl ester

Bis(dibenzylidineacetone)palladium (17 mg, 0.03 mmol) and(2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (35 mg, 0.09mmol) were added to dry toluene (5 mL purged with argon) and stirred for15 minutes under argon. Potassium tert-butoxide (166 mg, 1.48 mmol),6-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (176mg, 0.74 mmol) and (4-Bromo-2,6-dimethylphenyl)-carbamic acid ethylester (200 mg, 0.74 mmol) were then added and the reaction mixture wasstirred at 80° C. overnight. The reaction mixture was then cooled toroom temperature filtered through silica gel and purified by preparativethin layer chromatography (DCM 100%) to give the desired compound as asolid.

¹H NMR (DMSO-d₆, 400 MHz) δ 1.23 (t, J=7.2 Hz, 3H), 2.12 (s, 6H), 3.0(t, J=6.4 Hz, 2H), 3.52 (t, J=6.3 Hz, 2H), 4.08 (q, J=13.6, 8.3 Hz, 2H),4.42 (s, 2H) 6.73 (s, 2H), 7.46 (d, J=7.4, 1H), 7.54 (m, 2H), 8.32 (s,1H).

Biological Results

Compounds of this invention formula were evaluated for activity towardpotassium channels in a cell-based Rb⁺ efflux assay This cellularbioassay is believed to faithfully represent the M current channelactivities identified with KCNQ2/3 heteromultimers. The most activecompounds of this invention have EC₅₀s in the single-digit nM range,which represents a 40- to 400-fold improvement over retigabine.Additionally, antiseizure activity in vivo was evaluated in a mousemaximal electroshock seizure (MES) model, and neurotoxicities weredetermined from a rotorod neurocognitive motor impairment model.

Methods: Rubidium Efflux Test

PC-12 cells were grown at 37° C. and 5% CO₂ in DMEM/F12 Medium(Dulbecco's Modified Eagle Medium with Nutrient Mix F-12, available fromInvitrogen of Carlsbad, Calif.), supplemented with 10% horse serum, 5%fetal bovine serum, 2 mM glutamine, 100 U/ml penicillin, and 100 U/mlstreptomycin. They were plated in poly-D-lysine-coated 96-well cellculture microplates at a density of 40,000 cells/well and differentiatedwith 100 ng/ml NGF-7s for 2-5 days. For the assay, the medium wasaspirated, and the cells were washed once with 0.2 ml in wash buffer (25mM HEPES, pH 7.4, 150 mM NaCl, 1 mM MgCl₂, 0.8 mM NaH₂PO₄, 2 mM CaCl₂).The cells were then loaded with 0.2 ml Rb⁺ loading buffer (wash bufferplus 5.4 mM RbCl₂, 5 mM glucose) and incubated at 37° C. for 2 h.Attached cells were quickly washed three times with buffer (same as Rb⁺loading buffer, but containing 5.4 mM KCl instead of RbCI) to removeextracellular Rb⁺. Immediately following the wash, 0.2 ml ofdepolarization buffer (wash buffer plus 15 mM KCl) with or withoutcompounds was added to the cells to activate efflux of potassium ionchannels. After incubation for 10 min at room temperature, thesupernatant was carefully removed and collected. Cells were lysed by theaddition of 0.2 ml of lysis buffer (depolarization buffer plus 0.1%Triton X-100) and the cell lysates were also collected. If collectedsamples were not immediately analyzed for Rb⁺ contents by atomicabsorption spectroscopy (see below), they were stored at 4° C. withoutany negative effects on. subsequent Rb⁺ analysis.

The concentrations of Rb⁺ in the supernatants (Rb⁺ _(Sup)) and the celllysates (Rb⁺ _(Lys)) were quantified using an ICR8000 flame atomicabsorption spectrometer (Aurora Biomed Inc., Vancouver, B.C.) underconditions defined by the manufacturer. Samples 0.05 ml in volume wereprocessed automatically from microtiter plates by dilution with an equalvolume of Rb⁺ sample analysis buffer and injection into an air—acetyleneflame. The amount of Rb⁺ in the sample was measured by absorption at 780nm using a hollow cathode lamp as light source and a PMT detector. Acalibration curve covering the range 0-5 mg/L Rb⁺ in sample analysisbuffer was generated with each set of plates. The percent Rb⁺ efflux (F)was defined by

F=[Rb⁺ _(Sup)/(Rb⁺ _(Sup)+Rb⁺ _(Lys))]×100%.

where the F_(c) is the efflux in the presence of compound indepolarization buffer, F_(b) is the efflux in basal buffer, and F_(s) isthe efflux in depolarization buffer, and F_(c) is the efflux in thepresence of compound in depolarization buffer. The efflux (F) andcompound concentration relationship was plotted to calculate an EC₅₀value, a compound's concentration for 50% of maximal Rb⁺ efflux, Theresults are shown below.

Maximal Electroshock Seizure (MES) and Acute Toxicity Tests MES Test

The MES testing protocol is based on procedures established at theNational Institute of Neurological Disorders and Stroke in conjunctionwith the Anticonvulsant Screening Program (ASP) at the University ofUtah (White, H. S., Woodhead, J. H., Wilcox, K. S., Stables, J. P.,Kupferberg, H. J and Wolf, H. H. 2002. “General Principles: Discoveryand Preclinical Development of Antiepileptic Drugs,” in AntiepilepticDrugs, 5th Edition, R. H. Levy, ed.; R. H. Mattson, B. S. Meldrum, andE. Perucca. Philadelphia, Lippincott Williams & Wilkins.), The goal ofthe test rapid identification and characterization of the in vivoanticonvulsant activity of any compounds that have been shown active inPC-12 cellular based Rb⁺ efflux assay.

Adult male CF-I albino mice (18-25 g, Charles River Laboratories) areexclusively used for in-house MES screen of compounds. MaleSprague-Dawley albino rats (100-125 g, Charles River Laboratories) arealso used to test anticonvulsant compounds. Variability of test outcomesis reduced by using animals of the same sex, age, and weight. Animalsare permitted to rest and recover from transit for at least 48 hr priorto experimentation. Animals are used for AED testing only once. In someinstances, the animals may be anesthetized prior to blood collectionand/or whole brain extraction for pharmacokinetic assay. All animals aremaintained and handled as outlined in standard animal care guidelines.

In the experiments, testing compounds are prepared as suspensions in0.5% methyl cellulose (Sigma, Cat #M0512, Viscosity 4000 cP at 20° C.)in water, regardless of solubility. Dry powder compounds are initiallyground with a glass rod in a test tube in several drops of methylcellulose to create a paste and to break down any large chunks. Afterseveral minutes of grinding, the volume of the suspension is increasedto the final concentration desired. The suspension is then sonicatedusing a Branson sonicator model 3510 in a water bath at room temperaturefor 15 minutes. Compound suspensions are further vortexed prior toanimal dosing. In some of the cases, DMSO is used to initiallysolubilize compounds in small volumes and then this solution is added tothe 0.5% methyl cellulose solution, in order to create more even andless aggregated compound suspensions. The final concentration of DMSO is3.75%, an amount with no apparent toxicity or neuroprotective effects inour usual rotarod and MES tests. Methyl cellulose/DMSO compoundsuspensions are identically prepared for intraperitoneally (i.p.) tomice or orally (p.o.) to rat dosing.

Initially the animals are weighed with an electronic scale and thenmarked. Data recording sheets are generated for each compoundassessment. Mice or rats are dosed with the compound suspension at 0.01mL/g of body weight. The typical injection volume range is between180-250 μl for mice. Compounds are dosed by i.p. to mice using a 25 or22 gauge needle, depending on the viscosity of the suspension. Rats arep.o. dosed using a flexible feeding tube, typically starting at acompound dose of 5 mg/kg.

A Rodent Electroconvulsive Stimulator (Model 200, Hamit-Darvin-Freesh,Snow Canyon Clinic, Ivins, Utah) is used for MES testing. A 60-Hzalternating current (50 mA for mice; 150 mA for rats) is delivered for0.2 seconds through corneal electrodes to the mice. A drop of 0.5%tetracaine (Sigma, Cat. #T-7508) solution is placed on the eye prior tocurrent delivery. The electrodes are subsequently placed gently onto theeyes of the animal and the electrical shock is initiated by triggeringthrough a foot-pedal activator. The animals are restrained by hand andgently released as the shock is delivered and the seizure commences.Animals are monitored for hind limb tonic extension as the end point forthis test. Current delivery is recorded as a measure of overallseizure-induction potential. Electrical current delivery can vary fromapproximately 30-55 mA (mice) or 90-160 mA (rats) depending on impedancein the animal and quality of the current delivery (ie. correct placementof the electrodes on the cornea). Seizures will be successfully inducedin control animals throughout this current range. Tonic extension isconsidered abolished if the hind limbs fail to become fully extended at180° with the plane of the body. Lack of tonic extension suggests thatthe test compound has prevented the spread of seizure discharge throughneural tissue. Although unnecessary in mice, the rats are pre-screenedfor seizure induction potential using the MES 24 hr prior to compounddosing and the subsequent MES test. A success rate of 92-100% has beendetermined for the rat seizure induction potential. Rats that fail todevelop tonic/clonic seizures during the pre-screening are not used fordrug testing.

For a compound testing, time-to-peak effect studies are initiallyperformed using 0.5, 1, 2, 4, 8 and 24 hr time points, typically using asingle 5 or 25 mg/kg dose. The determined time-to-peak effect is usedfor further titration of a compound's potency (ED₅₀, the dose of a drugthat protects 50% of animals from electrical induced seizure) in bothmouse and rat models. For titrations, 8 animals are used perconcentration and dose (normal 5 concentrations) is varied until a fulldose response curve can be obtained. Probit analysis (ASP method) ornon-linear regression analysis on. Graph Pad (constraining the lowerdose/effect value) is used to calculate an ED₅₀ value for the testcompound.

Rotarod Test

Prior to MES testing, compound dosed mice are scrutinized for abnormalneurologic status as defined by motor impairment on a slowly turning (6rpm) rotarod apparatus (Model 755, Series 8, IITC Life Sciences,Woodland Hills, Calif.). The inability of a mouse to maintain itsbalance on the rotarod over a period of one minute (three falls=failure)signifies motor impairment and hence acute toxicity. These measurementsare done at the same time points as the MES assay. Untreated normal miceare able to maintain balance on the rotarod for at least one minutewithout falling. Median toxicity of a compound (TD₅₀, the dose of a drugthat results in motor impairment in 50% of animals) is determined.

In a murine MES model of epilepsy, compound A below cause significantinhibition of seizures with and ED50 of 2.2 mg/kg with a 95% confidencelevel of 1.06-2.89 mg/kg when dosed orally 2 hours prior to testing.

Minimal motor impairment as judged from the behavioral rotarod model wasobserved with a TD₅₀ value of 12.6 mg/kg. Similarly, a rat MES model ofepilepsy, KCNQ2/3 activator compound A cause statistically significantinhibition of seizures with an ED₅₀ of 1.1 mg/kg when dosed orally 1hour prior to testing. These results indicate compound A can beadministered as an anticonvulsant.

Open Field Test

Before MES test, compound treated rats are visually observed for acutetoxicity signs for approximately one minute in the open field test.Here, rats are gently placed into a plexiglass enclosure and aremonitored for behavior consistent with toxicity including ataxia,trembling, hypoactivity (including failure to seek the walls),hypersensitivity, lack of exploratory behavior and lack of avoidance ofthe open area. Typically if the rats exhibits two or more of theseabnormal behaviors they are scored as toxic. Motor impairment, as judgedby this test was not observed in the rat model and generated a TD₅₀value of greater than 5 mg/kg.

TABLE 1 ACTIVITIES OF EXEMPLARY COMPOUNDS Mouse ED₅₀ Rat ED₅₀ ActivityCOMPOUND (mg/kg) (mg/kg) EC₅₀

γ NA B

γ NA B

β NA C

γ NA C

β NA B

β α C

β NA B

γ NA B

γ NA B

γ NA B

α α B

γ NA A

NA NA C

β NA C

γ NA C

β NA B

β NA C

γ NA B

NA NA D

γ NA D

β NA D

γ NA D

α α B

β NA B

γ NA B

α α C

β NA D

γ NA D

NA NA D

NA NA C

NA NA D Legend: A: EC₅₀ ≦ 1 nM; B: = 1 nM < EC₅₀ ≦ nM; C: 10 nM < EC₅₀nM; D: 50 nM < EC₅₀ ≦ 500 nM α: 0.12 < ED50 ≦ 1.2 β: 0.12 < ED50 ≦ 1.2γ: 12 < ED50

Studies of KCNQ213 opening activity and KCNQ subtype selectivity usingelectrophysiological patch clamp in Xenopus oocytes

KCNQ potassium channels can be found in the heart, nervous tissue, andmany epithelia. KCNQ1 can form a homotetrameric potassium channel thatis coupled with an accessory β subunit, KCNE1 to generate I_(Ks)current. This potassium current is responsible for the slow component ofthe delayed rectifier potassium current that contributes to therepolarization of the cardiac action potential [Sanguinetti et al.Nature 384:80-83 (1996)]. KCNQ2, KCNQ3 and KCNQ5 are mainly found in thenervous system and they colocalize in several neuronal populations[Cooper et al. Proc. Natl. Acad. Sci. 97:4914-4919 (2000)]. Thesesubunits can form functional tetrameric potassium channels in theappropriate combinations and produce the M-type potassium current. KCNQ4is found to mainly express in sensory outer hair cells and gives rise toa M-like current similar to these generated by KCNQ1, KCNQ2 and KCNQ3channels but with a slower activation kinetics [Shieh et al Pharmacol.Rev. 52:557-593 (2000)].

Expression in Xenopus laevis Oocytes

Female Xenopus laevis extracted ovaries were purchased from eNASCO(LM00935MX, eNASCO Fort Atkinson, Wis.). Following manual dissection ofthe oocytes into smaller groups, the oocytes were defolliculated byenzymatic treatment with callagenase type 2 (LS004177, Worthington,Lakewood, N.J.) for 1½ hour in the presence of calcium-free Culture Bathsolution (88 mM NaCl, 1 mM KCI, 0.82 mM MgSO_(4,) 2.4 mM NaHCO₃, and 5mM HEPES, pH 7.5). Oocytes were then kept in supplemented Culture Bathsolution (88 mM NaCI, 1 mM KCl, 0.82 mM MgSO_(4,) 0.9 mM CaCl₂, 2.4 mMNaHCO₃, 1 mM sodium pyruvate, 0.05 mg/ml Geneticin, 100 U/ml penicillin,0.1 mg/ml streptomycin and 5 mM HEPES, pH 7.5) at 19° C. for 24 hoursbefore injection of cRNA. Approximately 50 nl cRNA (about 50 ng) wasinjected for KCNQ1, KCNQ4, and KCNQ5 using a Nanoject microinjector(Drummond, Broomall, Pa., USA). For co-expression of KCNQ2 and KCNQ3 andof KCNQ1 and KCNE1, cRNA's were mixed in equal molar ratios beforeinjection of approximately 50 nl. The mixtures contained about 10+10 ngand 12.5+2.5 ng cRNA, respectively. The smaller amounts are neededbecause larger currents arise when KCNQ2/KCNQ3 and KCNQI/KCNE1 areco-expressed. Oocytes were kept in Culture Barth solution at 19° C.which was changed daily and currents were recorded after 3 to 5 days.

Electrophysiology

KCNQ channel currents expressed in Xenopus laevis oocytes were recordedusing a two-electrode voltage-clamp. The recordings were made at roomtemperature in recording solution (96 mM NaCl, 2 mM KCl, 1 mM MgCl_(2,)1.8 mM CaCl₂, and 5 mM HEPES, pH 7.5) using a two-electrodevoltage-clamp amplifier (OC-725C, Warner Instrument, Hamden, Conn.,USA). The oocytes were placed in custom built perfusion chambersconnected to a continuous flow system and impaled with a currentelectrode and a voltage-clamp electrode pulled from borosilicate glasson a Flaming/Brown Micropipette Puller (Sutter Instruments Co, Novato,Calif., USA). Recording electrodes were filled with 3 M KCl and had aresistance of 0.5 to 2.5 MΩ

Compounds

All compounds were dissolved in DMSO to obtain concentrated stocksolutions. On the day of electrophysiological experiments the stocksolutions were thawed and diluted in recording solution to their finalconcentrations. The final DMSO concentration never exceeded 0.1%.Compound delivery was performed using a custom built multi-barrelapparatus connected to the flow system.

Calculations

Data were acquired by means of an Axograph X software (AxographScientific, Sydney, AU) and analyzed using Graph Pad Prism (GraphPadSoftware Inc., CA, USA).

Concentration—response curves were constructed by plotting the increasein steady-state current expressed in percentages as a function of drugconcentration. During the course of the experiment, while variousconcentrations of the drug were being dosed, the resting voltage washeld at −90 mV and pulsed to −60 mV, −40 mV, and −50 mV for 5 s forKCNQ2/KCNQ3, KCNQ4 and KCNQ5 channels respectively. The plot was thenfitted to a Hill function:

Response=R2+(R1−R2)/[1+(C/EC ₅₀)̂nH]

where R1 is the initial response, R2 is the maximum response, C is thedrug concentration and nH is the slope (Hill coefficient) of the curve.

The efficacy of compounds of this invention in comparison withRetigabine (as a positive control) was determined by recording thesteady current using the above voltage protocol for the channels in thepresence of the EC₇₅ of the drugs. After steady channel current wasrecorded in the presence of Retigabine at its EC75, recorded oocyte waswashed with the recording solution until its steady current returned toits normal level without the presence of any drugs. Then the channelsteady current was recorded in the presence of the test compound at itsEC₇₅. The percent efficacy was then expressed as:

% efficacy=(C2/C 1)×100

where C2 is the recorded steady current in the presence of follow-oncompound at its EC₇₅ and C1 is the recorded steady current in thepresence of Retigabine at its EC₇₅.

The KCNQ subtype selectivity for the KCNQ family expressed in oocytesfor exemplary compound A and retigabine is summarized in Table 2.

TABLE 2 KCNQ Selectivity: Oocyte Expression KCNQ2/3 KCNQ4 KCNQ5 KCNQ1KCNQ1/NE1 EC50 (mM) Block at 10 mM Efficacy Relative to RetigabineCompound (%) (%)

12 4.3    2.4 100  22 100  15 100

 0 3.5    0.35 143    0.63 100    0.35 100

For compound A shown in Table 1, the percent inhibition of KCNQ1 andKCNQ1/NEI channels were 0% and 3.5%, respectively. KCNQ5 was determinedto be 0.35 μM, 0.63 μM and 0.35 μM, respectively. Thus, compound Aexhibits selective potency within the KCNQ superfamily against channelsexpressed in the nervous system and inner ear and while not affectingchannels expressed in the heart.

KCNQ2 Selectivity

Using natively expressed M-currents present in differentiatedpheochromocytoma (PC-12) cells and CHO cells transfected with KCNQ2 andhERG potassium channels, the in vitro activity of compound A onpotassium ion efflux was determined.

The EC₅₀ values for retigabine and compound A on currents produced inPC-12 cells were determined on two separate occasions in triplicate. Theresults are shown in Table 3 below.

TABLE 3 Compound Average EC₅₀ value (nM)

292

15

The EC50 values for retigabine and compound A on the activation of KCNQ2channels expressed in CHO cells were determined on three separateoccasions in triplicate. The results are shown in Table 4 below.

TABLE 4 Compound Average EC₅₀ value (nM)

291

11

The effect of terfenadine and compound A was assessed against hERGchannels expressed in CHO cells. Experiments were run in triplicate. Theresults are shown below in Table 5.

TABLE 5 Compound EC₅₀ Value (μM) Max Inhibition @ 30 μM (%) terfenadine1.6 82

>30 −0.1

The results shown in Tables 3-5 above indicate good selectivity andactivity profile of compound A with respect to potency targeting KCNQ2.

Finally, an in vivo study of compound A was conducted, includingpharmacokinetic/pharmacodynamic (PK/PD) responses at three differentdose levels in a rat model. These results are summarized in FIGS. 1 a-1c. These figures indicate the brain and plasma concentrations ofcompound A as well as the MES effect at three different dosages, 0.75mg/kg, 1.5 mg/kg, and 3.0 mg/kg.

1. A method of treating or preventing a disease, disorder, or conditionthat is affected by modulation of at least one potassium ion channelselected from KCNQ2/3, KCNQ4, and KCNQ5 in a patient comprisingadministering compound A:

in an amount of from about 10 mg to about 2000 mg per day to a patient.2. Compound A: